2024
Ondrisova, Laura; Seda, Vaclav; Hlavac, Krystof; Pavelkova, Petra; Hoferkova, Eva; Chiodin, Giorgia; Kostalova, Lenka; Pavlasova, Gabriela Mladonicka; Filip, Daniel; Vecera, Josef; Zeni, Pedro Faria; Oppelt, Jan; Kahounova, Zuzana; Vichova, Rachel; Soucek, Karel; Panovska, Anna; Plevova, Karla; Pospisilova, Sarka; Simkovic, Martin; Vrbacky, Filip; Lysak, Daniel; Fernandes, Stacey M.; Davids, Matthew S.; Maiques-Diaz, Alba; Charalampopoulou, Stella; Martin-Subero, Jose I.; Brown, Jennifer R.; Doubek, Michael; Forconi, Francesco; Mayer, Jiri; Mraz, Marek
FoxO1/Rictor axis induces a non-genetic adaptation to Ibrutinib via Akt activation in chronic lymphocytic leukemia. Journal Article
In: The Journal of clinical investigation, pp. e173770, 2024, ISSN: 1558-8238 0021-9738, (Place: United States).
Abstract | Links | BibTeX | Tags: Drug therapy, Hematology, Leukemias, Oncology, Signal Transduction
@article{ondrisova_foxo1rictor_2024,
title = {FoxO1/Rictor axis induces a non-genetic adaptation to Ibrutinib via Akt activation in chronic lymphocytic leukemia.},
author = {Laura Ondrisova and Vaclav Seda and Krystof Hlavac and Petra Pavelkova and Eva Hoferkova and Giorgia Chiodin and Lenka Kostalova and Gabriela Mladonicka Pavlasova and Daniel Filip and Josef Vecera and Pedro Faria Zeni and Jan Oppelt and Zuzana Kahounova and Rachel Vichova and Karel Soucek and Anna Panovska and Karla Plevova and Sarka Pospisilova and Martin Simkovic and Filip Vrbacky and Daniel Lysak and Stacey M. Fernandes and Matthew S. Davids and Alba Maiques-Diaz and Stella Charalampopoulou and Jose I. Martin-Subero and Jennifer R. Brown and Michael Doubek and Francesco Forconi and Jiri Mayer and Marek Mraz},
doi = {10.1172/JCI173770},
issn = {1558-8238 0021-9738},
year = {2024},
date = {2024-10-01},
journal = {The Journal of clinical investigation},
pages = {e173770},
abstract = {BTK inhibitor therapy induces peripheral blood lymphocytosis in chronic lymphocytic leukemia (CLL) lasting for several months. It remains unclear whether non-genetic adaptation mechanisms exist, allowing CLL cells' survival during BTK inhibitor-induced lymphocytosis and/or playing a role in therapy resistance. We show that in approximately 70 % of CLL cases, ibrutinib treatment in vivo increases Akt activity above pre-therapy levels within several weeks, leading to compensatory CLL cell survival and a more prominent lymphocytosis on therapy. Ibrutinib-induced Akt phosphorylation (pAktS473) is caused by the upregulation of FoxO1 transcription factor, which induces expression of Rictor, an assembly protein for mTORC2 protein complex that directly phosphorylates Akt at serine 473 (S473). Knock-out or inhibition of FoxO1 or Rictor led to a dramatic decrease in Akt phosphorylation and growth disadvantage for malignant B cells in the presence of ibrutinib (or PI3K inhibitor idelalisib) in vitro and in vivo. FoxO1/Rictor/pAktS473 axis represents an early non-genetic adaptation to BCR inhibitor therapy not requiring PI3Kδ or BTK kinase activity. We further demonstrate that FoxO1 can be targeted therapeutically, and its inhibition induces CLL cells' apoptosis alone or in combination with BTK inhibitors (ibrutinib, acalabrutinib, pirtobrutinib) and blocks their proliferation triggered by T-cell factors (CD40L, IL-4, and IL-21).},
note = {Place: United States},
keywords = {Drug therapy, Hematology, Leukemias, Oncology, Signal Transduction},
pubstate = {published},
tppubtype = {article}
}
Valcikova, Barbora; Vadovicova, Natalia; Smolkova, Karolina; Zacpalova, Magdalena; Krejci, Pavel; Lee, Shannon; Rauch, Jens; Kolch, Walter; Kriegsheim, Alexander; Dorotikova, Anna; Andrysik, Zdenek; Vichova, Rachel; Vacek, Ondrej; Soucek, Karel; Uldrijan, Stjepan
eIF4F controls ERK MAPK signaling in melanomas with BRAF and NRAS mutations. Journal Article
In: Proceedings of the National Academy of Sciences of the United States of America, vol. 121, no. 44, pp. e2321305121, 2024, ISSN: 1091-6490 0027-8424, (Place: United States).
Abstract | Links | BibTeX | Tags: *Eukaryotic Initiation Factor-4F/metabolism/genetics, *GTP Phosphohydrolases/metabolism/genetics, *MAP Kinase Signaling System/genetics, *Melanoma/genetics/metabolism/pathology, *Membrane Proteins/metabolism/genetics, *Mutation, *Proto-Oncogene Proteins B-raf/genetics/metabolism, Animals, Cell Line, Dual Specificity Phosphatase 6/metabolism/genetics, DUSP6, eIF4F, ERK, Extracellular Signal-Regulated MAP Kinases/metabolism, Humans, MAP kinase, Melanoma, Mice, Tumor
@article{valcikova_eif4f_2024,
title = {eIF4F controls ERK MAPK signaling in melanomas with BRAF and NRAS mutations.},
author = {Barbora Valcikova and Natalia Vadovicova and Karolina Smolkova and Magdalena Zacpalova and Pavel Krejci and Shannon Lee and Jens Rauch and Walter Kolch and Alexander Kriegsheim and Anna Dorotikova and Zdenek Andrysik and Rachel Vichova and Ondrej Vacek and Karel Soucek and Stjepan Uldrijan},
doi = {10.1073/pnas.2321305121},
issn = {1091-6490 0027-8424},
year = {2024},
date = {2024-10-01},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {121},
number = {44},
pages = {e2321305121},
abstract = {The eIF4F translation initiation complex plays a critical role in melanoma resistance to clinical BRAF and MEK inhibitors. In this study, we uncover a function of eIF4F in the negative regulation of the rat sarcoma (RAS)/rapidly accelerated fibrosarcoma (RAF)/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) signaling pathway. We demonstrate that eIF4F is essential for controlling ERK signaling intensity in treatment-naïve melanoma cells harboring BRAF or NRAS mutations. Specifically, the dual-specificity phosphatase DUSP6/MKP3, which acts as a negative feedback regulator of ERK activity, requires continuous production in an eIF4F-dependent manner to limit excessive ERK signaling driven by oncogenic RAF/RAS mutations. Treatment with small-molecule eIF4F inhibitors disrupts the negative feedback control of MAPK signaling, leading to ERK hyperactivation and EGR1 overexpression in melanoma cells in vitro and in vivo. Furthermore, our quantitative analyses reveal a high spare signaling capacity in the ERK pathway, suggesting that eIF4F-dependent feedback keeps the majority of ERK molecules inactive under normal conditions. Overall, our findings highlight the crucial role of eIF4F in regulating ERK signaling flux and suggest that pharmacological eIF4F inhibitors can disrupt the negative feedback control of MAPK activity in melanomas with BRAF and NRAS activating mutations.},
note = {Place: United States},
keywords = {*Eukaryotic Initiation Factor-4F/metabolism/genetics, *GTP Phosphohydrolases/metabolism/genetics, *MAP Kinase Signaling System/genetics, *Melanoma/genetics/metabolism/pathology, *Membrane Proteins/metabolism/genetics, *Mutation, *Proto-Oncogene Proteins B-raf/genetics/metabolism, Animals, Cell Line, Dual Specificity Phosphatase 6/metabolism/genetics, DUSP6, eIF4F, ERK, Extracellular Signal-Regulated MAP Kinases/metabolism, Humans, MAP kinase, Melanoma, Mice, Tumor},
pubstate = {published},
tppubtype = {article}
}
Procházková, Jiřina; Fedr, Radek; Hradilová, Barbora; Kvokačková, Barbora; Slavík, Josef; Kováč, Ondrej; Machala, Miroslav; Fabian, Pavel; Navrátil, Jiří; Kráčalíková, Simona; Levková, Monika; Ovesná, Petra; Bouchal, Jan; Souček, Karel
In: Journal of lipid research, vol. 65, no. 9, pp. 100609, 2024, ISSN: 1539-7262 0022-2275, (Place: United States).
Abstract | Links | BibTeX | Tags: *Breast Neoplasms/metabolism/pathology, *Epithelial-Mesenchymal Transition, *Glycosphingolipids/metabolism/analysis, *Single-Cell Analysis/methods, Breast cancer, Epithelial Cells, Female, Glycosphingolipids, Humans, Phenotype, phenotypic plasticity, stromal-like cells, surface profiling
@article{prochazkova_single-cell_2024,
title = {Single-cell profiling of surface glycosphingolipids opens a new dimension for deconvolution of breast cancer intratumoral heterogeneity and phenotypic plasticity.},
author = {Jiřina Procházková and Radek Fedr and Barbora Hradilová and Barbora Kvokačková and Josef Slavík and Ondrej Kováč and Miroslav Machala and Pavel Fabian and Jiří Navrátil and Simona Kráčalíková and Monika Levková and Petra Ovesná and Jan Bouchal and Karel Souček},
doi = {10.1016/j.jlr.2024.100609},
issn = {1539-7262 0022-2275},
year = {2024},
date = {2024-09-01},
journal = {Journal of lipid research},
volume = {65},
number = {9},
pages = {100609},
abstract = {Glycosylated sphingolipids (GSLs) are a diverse group of cellular lipids typically reported as being rare in normal mammary tissue. In breast cancer (BCa), GSLs have emerged as noteworthy markers associated with breast cancer stem cells, mediators of phenotypic plasticity, and contributors to cancer cell chemoresistance. GSLs are potential surface markers that can uniquely characterize the heterogeneity of the tumor microenvironment, including cancer cell subpopulations and epithelial-mesenchymal plasticity (EMP). In this study, mass spectrometry analyses of the total sphingolipidome in breast epithelial cells and their mesenchymal counterparts revealed increased levels of Gb3 in epithelial cells and significantly elevated GD2 levels in the mesenchymal phenotype. To elucidate if GSL-related epitopes on BCa cell surfaces reflect EMP and cancer status, we developed and rigorously validated a 12-color spectral flow cytometry panel. This panel enables the simultaneous detection of native GSL epitopes (Gb3, SSEA1, SSEA3, SSEA4, and GD2), epithelial-mesenchymal transition markers (EpCAM, TROP2, and CD9), and lineage markers (CD45, CD31, and CD90) at the single-cell level. Next, the established panel was used for the analysis of BCa primary tumors and revealed surface heterogeneity in SSEA1, SSEA3, SSEA4, GD2, and Gb3, indicative of native epitope presence also on non-tumor cells. These findings further highlighted the phenotype-dependent alterations in GSL surface profiles, with differences between epithelial and stromal cells in the tumor. This study provides novel insights into BCa heterogeneity, shedding light on the potential of native GSL-related epitopes as markers for EMP and cancer status in fresh clinical samples. The developed single-cell approach offers promising avenues for further exploration.},
note = {Place: United States},
keywords = {*Breast Neoplasms/metabolism/pathology, *Epithelial-Mesenchymal Transition, *Glycosphingolipids/metabolism/analysis, *Single-Cell Analysis/methods, Breast cancer, Epithelial Cells, Female, Glycosphingolipids, Humans, Phenotype, phenotypic plasticity, stromal-like cells, surface profiling},
pubstate = {published},
tppubtype = {article}
}
Besse, Andrej; Sedlarikova, Lenka; Buechler, Lorina; Kraus, Marianne; Yang, Chieh-Hsiang; Strakova, Nicol; Soucek, Karel; Navratil, Jiri; Svoboda, Marek; Welm, Alana L.; Joerger, Markus; Driessen, Christoph; Besse, Lenka
HIV-protease inhibitors potentiate the activity of carfilzomib in triple-negative breast cancer. Journal Article
In: British journal of cancer, vol. 131, no. 5, pp. 918–930, 2024, ISSN: 1532-1827 0007-0920, (Place: England).
Abstract | Links | BibTeX | Tags: *ATP Binding Cassette Transporter, *Bortezomib/pharmacology, *Drug Synergism, *HIV Protease Inhibitors/pharmacology, *Lopinavir/pharmacology, *Nelfinavir/pharmacology, *Oligopeptides/pharmacology, *Triple Negative Breast Neoplasms/drug therapy/pathology, *Unfolded Protein Response/drug effects, Antineoplastic Combined Chemotherapy Protocols/pharmacology, Apoptosis/drug effects, ATP Binding Cassette Transporter, Cell Line, Endoplasmic Reticulum Stress/drug effects, Female, Humans, Member 2/metabolism/antagonists & inhibitors, Neoplasm Proteins/antagonists & inhibitors/metabolism, Proteasome Inhibitors/pharmacology, Subfamily B/metabolism, Subfamily G, Tumor, X-Box Binding Protein 1/metabolism/genetics
@article{besse_hiv-protease_2024,
title = {HIV-protease inhibitors potentiate the activity of carfilzomib in triple-negative breast cancer.},
author = {Andrej Besse and Lenka Sedlarikova and Lorina Buechler and Marianne Kraus and Chieh-Hsiang Yang and Nicol Strakova and Karel Soucek and Jiri Navratil and Marek Svoboda and Alana L. Welm and Markus Joerger and Christoph Driessen and Lenka Besse},
doi = {10.1038/s41416-024-02774-9},
issn = {1532-1827 0007-0920},
year = {2024},
date = {2024-09-01},
journal = {British journal of cancer},
volume = {131},
number = {5},
pages = {918–930},
abstract = {BACKGROUND: Resistance to chemotherapy is a major problem in the treatment of patients with triple-negative breast cancer (TNBC). Preclinical data suggest that TNBC is dependent on proteasomes; however, clinical observations indicate that the efficacy of proteasome inhibitors in TNBC may be limited, suggesting the need for combination therapies. METHODS: We compared bortezomib and carfilzomib and their combinations with nelfinavir and lopinavir in TNBC cell lines and primary cells with regard to their cytotoxic activity, functional proteasome inhibition, and induction of the unfolded protein response (UPR). Furthermore, we evaluated the involvement of sXBP1, ABCB1, and ABCG2 in the cytotoxic activity of drug combinations. RESULTS: Carfilzomib, via proteasome β5 + β2 inhibition, is more cytotoxic in TNBC than bortezomib, which inhibits β5 + β1 proteasome subunits. The cytotoxicity of carfilzomib was significantly potentiated by nelfinavir or lopinavir. Carfilzomib with lopinavir induced endoplasmic reticulum stress and pro-apoptotic UPR through the accumulation of excess proteasomal substrate protein in TNBC in vitro. Moreover, lopinavir increased the intracellular availability of carfilzomib by inhibiting carfilzomib export from cells that express high levels and activity of ABCB1, but not ABCG2. CONCLUSION: Proteasome inhibition by carfilzomib combined with nelfinavir/lopinavir represents a potential treatment option for TNBC, warranting further investigation.},
note = {Place: England},
keywords = {*ATP Binding Cassette Transporter, *Bortezomib/pharmacology, *Drug Synergism, *HIV Protease Inhibitors/pharmacology, *Lopinavir/pharmacology, *Nelfinavir/pharmacology, *Oligopeptides/pharmacology, *Triple Negative Breast Neoplasms/drug therapy/pathology, *Unfolded Protein Response/drug effects, Antineoplastic Combined Chemotherapy Protocols/pharmacology, Apoptosis/drug effects, ATP Binding Cassette Transporter, Cell Line, Endoplasmic Reticulum Stress/drug effects, Female, Humans, Member 2/metabolism/antagonists & inhibitors, Neoplasm Proteins/antagonists & inhibitors/metabolism, Proteasome Inhibitors/pharmacology, Subfamily B/metabolism, Subfamily G, Tumor, X-Box Binding Protein 1/metabolism/genetics},
pubstate = {published},
tppubtype = {article}
}
Drápela, Stanislav; Kvokačková, Barbora; Slabáková, Eva; Kotrbová, Anna; Gömöryová, Kristína; Fedr, Radek; Kurfürstová, Daniela; Eliáš, Martin; Študent, Vladimír Jr; Lenčéšová, Frederika; Ranjani, Ganji Sri; Pospíchalová, Vendula; Bryja, Vítězslav; Weerden, Wytske M.; Puhr, Martin; Culig, Zoran; Bouchal, Jan; Souček, Karel
Pre-existing cell subpopulations in primary prostate cancer tumors display surface fingerprints of docetaxel-resistant cells. Journal Article
In: Cellular oncology (Dordrecht, Netherlands), 2024, ISSN: 2211-3436 2211-3428, (Place: Netherlands).
Abstract | Links | BibTeX | Tags: CD95/Fas, Docetaxel resistance, Intratumoral heterogeneity, Plasticity, Prostate cancer, SSEA-4
@article{drapela_pre-existing_2024,
title = {Pre-existing cell subpopulations in primary prostate cancer tumors display surface fingerprints of docetaxel-resistant cells.},
author = {Stanislav Drápela and Barbora Kvokačková and Eva Slabáková and Anna Kotrbová and Kristína Gömöryová and Radek Fedr and Daniela Kurfürstová and Martin Eliáš and Vladimír Jr Študent and Frederika Lenčéšová and Ganji Sri Ranjani and Vendula Pospíchalová and Vítězslav Bryja and Wytske M. Weerden and Martin Puhr and Zoran Culig and Jan Bouchal and Karel Souček},
doi = {10.1007/s13402-024-00982-2},
issn = {2211-3436 2211-3428},
year = {2024},
date = {2024-08-01},
journal = {Cellular oncology (Dordrecht, Netherlands)},
abstract = {PURPOSE: Docetaxel resistance is a significant obstacle in the treatment of prostate cancer (PCa), resulting in unfavorable patient prognoses. Intratumoral heterogeneity, often associated with epithelial-to-mesenchymal transition (EMT), has previously emerged as a phenomenon that facilitates adaptation to various stimuli, thus promoting cancer cell diversity and eventually resistance to chemotherapy, including docetaxel. Hence, understanding intratumoral heterogeneity is essential for better patient prognosis and the development of personalized treatment strategies. METHODS: To address this, we employed a high-throughput single-cell flow cytometry approach to identify a specific surface fingerprint associated with docetaxel-resistance in PCa cells and complemented it with proteomic analysis of extracellular vesicles. We further validated selected antigens using docetaxel-resistant patient-derived xenografts in vivo and probed primary PCa specimens to interrogate of their surface fingerprint. RESULTS: Our approaches revealed a 6-molecule surface fingerprint linked to docetaxel resistance in primary PCa specimens. We observed consistent overexpression of CD95 (FAS/APO-1), and SSEA-4 surface antigens in both in vitro and in vivo docetaxel-resistant models, which was also observed in a cell subpopulation of primary PCa tumors exhibiting EMT features. Furthermore, CD95, along with the essential enzymes involved in SSEA-4 synthesis, ST3GAL1, and ST3GAL2, displayed a significant increase in patients with PCa undergoing docetaxel-based therapy, correlating with poor survival outcomes. CONCLUSION: In summary, we demonstrate that the identified 6-molecule surface fingerprint associated with docetaxel resistance pre-exists in a subpopulation of primary PCa tumors before docetaxel treatment. Thus, this fingerprint warrants further validation as a promising predictive tool for docetaxel resistance in PCa patients prior to therapy initiation.},
note = {Place: Netherlands},
keywords = {CD95/Fas, Docetaxel resistance, Intratumoral heterogeneity, Plasticity, Prostate cancer, SSEA-4},
pubstate = {published},
tppubtype = {article}
}
Němec, Václav; Remeš, Marek; Beňovský, Petr; Böck, Michael C.; Šranková, Eliška; Wong, Jong Fu; Cros, Julien; Williams, Eleanor; Tse, Lap Hang; Smil, David; Ensan, Deeba; Isaac, Methvin B.; Al-Awar, Rima; Gomolková, Regina; Ursachi, Vlad-Constantin; Fafílek, Bohumil; Kahounová, Zuzana; Víchová, Ráchel; Vacek, Ondřej; Berger, Benedict-Tilman; Wells, Carrow I.; Corona, Cesear R.; Vasta, James D.; Robers, Matthew B.; Krejci, Pavel; Souček, Karel; Bullock, Alex N.; Knapp, Stefan; Paruch, Kamil
Discovery of Two Highly Selective Structurally Orthogonal Chemical Probes for Activin Receptor-like Kinases 1 and 2. Journal Article
In: Journal of medicinal chemistry, vol. 67, no. 15, pp. 12632–12659, 2024, ISSN: 1520-4804 0022-2623, (Place: United States).
Abstract | Links | BibTeX | Tags: *Activin Receptors, Activin Receptors, Animals, Bone Morphogenetic Proteins/metabolism, Drug Discovery, Humans, Mice, Molecular Probes/chemistry, Protein Kinase Inhibitors/pharmacology/chemistry, Pyrazoles/chemistry/pharmacology/chemical synthesis, Signal Transduction/drug effects, Structure-Activity Relationship, Type I/antagonists & inhibitors/metabolism, Type II/metabolism/antagonists & inhibitors
@article{nemec_discovery_2024,
title = {Discovery of Two Highly Selective Structurally Orthogonal Chemical Probes for Activin Receptor-like Kinases 1 and 2.},
author = {Václav Němec and Marek Remeš and Petr Beňovský and Michael C. Böck and Eliška Šranková and Jong Fu Wong and Julien Cros and Eleanor Williams and Lap Hang Tse and David Smil and Deeba Ensan and Methvin B. Isaac and Rima Al-Awar and Regina Gomolková and Vlad-Constantin Ursachi and Bohumil Fafílek and Zuzana Kahounová and Ráchel Víchová and Ondřej Vacek and Benedict-Tilman Berger and Carrow I. Wells and Cesear R. Corona and James D. Vasta and Matthew B. Robers and Pavel Krejci and Karel Souček and Alex N. Bullock and Stefan Knapp and Kamil Paruch},
doi = {10.1021/acs.jmedchem.4c00629},
issn = {1520-4804 0022-2623},
year = {2024},
date = {2024-08-01},
journal = {Journal of medicinal chemistry},
volume = {67},
number = {15},
pages = {12632–12659},
abstract = {Activin receptor-like kinases 1-7 (ALK1-7) regulate a complex network of SMAD-independent as well as SMAD-dependent signaling pathways. One of the widely used inhibitors for functional investigations of these processes, in particular for bone morphogenetic protein (BMP) signaling, is LDN-193189. However, LDN-193189 has insufficient kinome-wide selectivity complicating its use in cellular target validation assays. Herein, we report the identification and comprehensive characterization of two chemically distinct highly selective inhibitors of ALK1 and ALK2, M4K2234 and MU1700, along with their negative controls. We show that both MU1700 and M4K2234 efficiently block the BMP pathway via selective in cellulo inhibition of ALK1/2 kinases and exhibit favorable in vivo profiles in mice. MU1700 is highly brain penetrant and shows remarkably high accumulation in the brain. These high-quality orthogonal chemical probes offer the selectivity required to become widely used tools for in vitro and in vivo investigation of BMP signaling.},
note = {Place: United States},
keywords = {*Activin Receptors, Activin Receptors, Animals, Bone Morphogenetic Proteins/metabolism, Drug Discovery, Humans, Mice, Molecular Probes/chemistry, Protein Kinase Inhibitors/pharmacology/chemistry, Pyrazoles/chemistry/pharmacology/chemical synthesis, Signal Transduction/drug effects, Structure-Activity Relationship, Type I/antagonists & inhibitors/metabolism, Type II/metabolism/antagonists & inhibitors},
pubstate = {published},
tppubtype = {article}
}
Kahounová, Zuzana; Pícková, Markéta; Drápela, Stanislav; Bouchal, Jan; Szczyrbová, Eva; Navrátil, Jiří; Souček, Karel
Correction: Circulating tumor cell-derived preclinical models: current status and future perspectives. Journal Article
In: Cell death & disease, vol. 15, no. 7, pp. 472, 2024, ISSN: 2041-4889, (Place: England).
@article{kahounova_correction_2024,
title = {Correction: Circulating tumor cell-derived preclinical models: current status and future perspectives.},
author = {Zuzana Kahounová and Markéta Pícková and Stanislav Drápela and Jan Bouchal and Eva Szczyrbová and Jiří Navrátil and Karel Souček},
doi = {10.1038/s41419-024-06825-0},
issn = {2041-4889},
year = {2024},
date = {2024-07-01},
journal = {Cell death & disease},
volume = {15},
number = {7},
pages = {472},
note = {Place: England},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Pícková, Markéta; Kahounová, Zuzana; Radaszkiewicz, Tomasz; Procházková, Jiřina; Fedr, Radek; Nosková, Michaela; Radaszkiewicz, Katarzyna Anna; Ovesná, Petra; Bryja, Vítězslav; Souček, Karel
Orthotopic model for the analysis of melanoma circulating tumor cells. Journal Article
In: Scientific reports, vol. 14, no. 1, pp. 7827, 2024, ISSN: 2045-2322, (Place: England).
Abstract | Links | BibTeX | Tags: *Melanoma/pathology, *Neoplastic Cells, *Skin Neoplasms/pathology, Animals, Circulating tumor cells, Circulating/pathology, Flow Cytometry, Humans, In vivo model, Lymphatic Metastasis, Melanoma, Metastasis, Tumorectomy
@article{pickova_orthotopic_2024,
title = {Orthotopic model for the analysis of melanoma circulating tumor cells.},
author = {Markéta Pícková and Zuzana Kahounová and Tomasz Radaszkiewicz and Jiřina Procházková and Radek Fedr and Michaela Nosková and Katarzyna Anna Radaszkiewicz and Petra Ovesná and Vítězslav Bryja and Karel Souček},
doi = {10.1038/s41598-024-58236-y},
issn = {2045-2322},
year = {2024},
date = {2024-04-01},
journal = {Scientific reports},
volume = {14},
number = {1},
pages = {7827},
abstract = {Metastatic melanoma, a highly lethal form of skin cancer, presents significant clinical challenges due to limited therapeutic options and high metastatic capacity. Recent studies have demonstrated that cancer dissemination can occur earlier, before the diagnosis of the primary tumor. The progress in understanding the kinetics of cancer dissemination is limited by the lack of animal models that accurately mimic disease progression. We have established a xenograft model of human melanoma that spontaneously metastasizes to lymph nodes and lungs. This model allows precise monitoring of melanoma progression and is suitable for the quantitative and qualitative analysis of circulating tumor cells (CTCs). We have validated a flow cytometry-based protocol for CTCs enumeration and isolation. We could demonstrate that (i) CTCs were detectable in the bloodstream from the fourth week after tumor initiation, coinciding with the lymph node metastases appearance, (ii) excision of the primary tumor accelerated the formation of metastases in lymph nodes and lungs as early as one-week post-surgery, accompanied by the increased numbers of CTCs, and (iii) CTCs change their surface protein signature. In summary, we present a model of human melanoma that can be effectively utilized for future drug efficacy studies.},
note = {Place: England},
keywords = {*Melanoma/pathology, *Neoplastic Cells, *Skin Neoplasms/pathology, Animals, Circulating tumor cells, Circulating/pathology, Flow Cytometry, Humans, In vivo model, Lymphatic Metastasis, Melanoma, Metastasis, Tumorectomy},
pubstate = {published},
tppubtype = {article}
}
Hýžďalová, Martina; Procházková, Jiřina; Straková, Nicol; Pěnčíková, Kateřina; Strapáčová, Simona; Slováčková, Jana; Kajabová, Simona; Líbalová, Helena; Topinka, Jan; Kabátková, Markéta; Vondráček, Jan; Mollerup, Steen; Machala, Miroslav
In: Environmental toxicology and pharmacology, vol. 107, pp. 104424, 2024, ISSN: 1872-7077 1382-6689, (Place: Netherlands).
Abstract | Links | BibTeX | Tags: *Benzo(a)pyrene/toxicity, *Epithelial Cells/metabolism, 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin, Aryl hydrocarbon receptor, Aryl Hydrocarbon/genetics/metabolism, Benzo[a]pyrene, DNA Damage, Epithelial-Mesenchymal Transition, Human bronchial epithelial cells, Humans, Ligands, Receptors
@article{hyzdalova_transcriptional_2024,
title = {Transcriptional and phenotypical alterations associated with a gradual benzo[a]pyrene-induced transition of human bronchial epithelial cells into mesenchymal-like cells.},
author = {Martina Hýžďalová and Jiřina Procházková and Nicol Straková and Kateřina Pěnčíková and Simona Strapáčová and Jana Slováčková and Simona Kajabová and Helena Líbalová and Jan Topinka and Markéta Kabátková and Jan Vondráček and Steen Mollerup and Miroslav Machala},
doi = {10.1016/j.etap.2024.104424},
issn = {1872-7077 1382-6689},
year = {2024},
date = {2024-04-01},
journal = {Environmental toxicology and pharmacology},
volume = {107},
pages = {104424},
abstract = {The role of benzo[a]pyrene (BaP), a prominent genotoxic carcinogen and aryl hydrocarbon receptor (AhR) ligand, in tumor progression remains poorly characterized. We investigated the impact of BaP on the process of epithelial-mesenchymal transition (EMT) in normal human bronchial epithelial HBEC-12KT cells. Early morphological changes after 2-week exposure were accompanied with induction of SERPINB2, IL1, CDKN1A/p21 (linked with cell cycle delay) and chemokine CXCL5. After 8-week exposure, induction of cell migration and EMT-related pattern of markers/regulators led to induction of further pro-inflammatory cytokines or non-canonical Wnt pathway ligand WNT5A. This trend of up-regulation of pro-inflammatory genes and non-canonical Wnt pathway constituents was observed also in the BaP-transformed HBEC-12KT-B1 cells. In general, transcriptional effects of BaP differed from those of TGFβ1, a prototypical EMT inducer, or a model non-genotoxic AhR ligand, TCDD. Carcinogenic polycyclic aromatic hydrocarbons could thus induce a unique set of molecular changes linked with EMT and cancer progression.},
note = {Place: Netherlands},
keywords = {*Benzo(a)pyrene/toxicity, *Epithelial Cells/metabolism, 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin, Aryl hydrocarbon receptor, Aryl Hydrocarbon/genetics/metabolism, Benzo[a]pyrene, DNA Damage, Epithelial-Mesenchymal Transition, Human bronchial epithelial cells, Humans, Ligands, Receptors},
pubstate = {published},
tppubtype = {article}
}
Procházková, Jiřina; Kahounová, Zuzana; Vondráček, Jan; Souček, Karel
Aryl hydrocarbon receptor as a drug target in advanced prostate cancer therapy - obstacles and perspectives. Journal Article
In: Transcription, pp. 1–20, 2024, ISSN: 2154-1272, (Place: United States).
Abstract | Links | BibTeX | Tags: antibody-drug conjugates, Aryl hydrocarbon receptor, castration resistance, Prostate cancer
@article{prochazkova_aryl_2024,
title = {Aryl hydrocarbon receptor as a drug target in advanced prostate cancer therapy - obstacles and perspectives.},
author = {Jiřina Procházková and Zuzana Kahounová and Jan Vondráček and Karel Souček},
doi = {10.1080/21541264.2024.2334106},
issn = {2154-1272},
year = {2024},
date = {2024-03-01},
journal = {Transcription},
pages = {1–20},
abstract = {Aryl hydrocarbon receptor (AhR) is a transcription factor that is primarily known as an intracellular sensor of environmental pollution. After five decades, the list of synthetic and toxic chemicals that activate AhR signaling has been extended to include a number of endogenous compounds produced by various types of cells via their metabolic activity. AhR signaling is active from the very beginning of embryonal development throughout the life cycle and participates in numerous biological processes such as control of cell proliferation and differentiation, metabolism of aromatic compounds of endogenous and exogenous origin, tissue regeneration and stratification, immune system development and polarization, control of stemness potential, and homeostasis maintenance. AhR signaling can be affected by various pharmaceuticals that may help modulate abnormal AhR signaling and drive pathological states. Given their role in immune system development and regulation, AhR antagonistic ligands are attractive candidates for immunotherapy of disease states such as advanced prostate cancer, where an aberrant immune microenvironment contributes to cancer progression and needs to be reeducated. Advanced stages of prostate cancer are therapeutically challenging and characterized by decreased overall survival (OS) due to the metastatic burden. Therefore, this review addresses the role of AhR signaling in the development and progression of prostate cancer and discusses the potential of AhR as a drug target for the treatment of advanced prostate cancer upon entering the phase of drug resistance and failure of first-line androgen deprivation therapy.Abbreviation: ADC: antibody-drug conjugate; ADT: androgen deprivation therapy; AhR: aryl hydrocarbon receptor; AR: androgen receptor; ARE: androgen response element; ARPI: androgen receptor pathway inhibitor; mCRPC: metastatic castration-resistant prostate cancer; DHT: 5a-dihydrotestosterone; FICZ: 6-formylindolo[3,2-b]carbazole; 3-MC: 3-methylcholanthrene; 6-MCDF: 6-methyl-1,3,8-trichlorodibenzofuran; MDSCs: myeloid-derived suppressor cells; PAHs: polycyclic aromatic hydrocarbons; PCa: prostate cancer; TAMs: tumor-associated macrophages; TF: transcription factor; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TME: tumor microenvironment; TRAMP: transgenic adenocarcinoma of the mouse prostate; TROP2: tumor associated calcium signal transducer 2.},
note = {Place: United States},
keywords = {antibody-drug conjugates, Aryl hydrocarbon receptor, castration resistance, Prostate cancer},
pubstate = {published},
tppubtype = {article}
}
Chrenková, Eva; Študentová, Hana; Holá, Kateřina; Kahounová, Zuzana; Hendrychová, Romana; Souček, Karel; Bouchal, Jan
Castration-resistant prostate cancer monitoring by cell-free circulating biomarkers. Journal Article
In: Frontiers in oncology, vol. 14, pp. 1394292, 2024, ISSN: 2234-943X, (Place: Switzerland).
Abstract | Links | BibTeX | Tags: biomarker, castration-resistant prostate cancer, liquid biopsy, progression monitoring, therapy response
@article{chrenkova_castration-resistant_2024,
title = {Castration-resistant prostate cancer monitoring by cell-free circulating biomarkers.},
author = {Eva Chrenková and Hana Študentová and Kateřina Holá and Zuzana Kahounová and Romana Hendrychová and Karel Souček and Jan Bouchal},
doi = {10.3389/fonc.2024.1394292},
issn = {2234-943X},
year = {2024},
date = {2024-01-01},
journal = {Frontiers in oncology},
volume = {14},
pages = {1394292},
abstract = {BACKGROUND: Prostate cancer is the second leading cause of male cancer-related deaths in Western countries, which is predominantly attributed to the metastatic castration-resistant stage of the disease (CRPC). There is an urgent need for better prognostic and predictive biomarkers, particularly for androgen receptor targeted agents and taxanes. METHODS: We have searched the PubMed database for original articles and meta-analyses providing information on blood-based markers for castration-resistant prostate cancer monitoring, risk group stratification and prediction of therapy response. RESULTS: The molecular markers are discussed along with the standard clinical parameters, such as prostate specific antigen, lactate dehydrogenase or C-reactive protein. Androgen receptor (AR) alterations are commonly associated with progression to CRPC. These include amplification of AR and its enhancer, point mutations and splice variants. Among DNA methylations, a novel 5-hydroxymethylcytosine activation marker of TOP2A and EZH2 has been identified for the aggressive disease. miR-375 is currently the most promising candidate among non-coding RNAs and sphingolipid analysis has recently emerged as a novel approach. CONCLUSIONS: The promising biomarkers have the potential to improve the care of metastatic prostate cancer patients, however, they need further validation for routine implementation.},
note = {Place: Switzerland},
keywords = {biomarker, castration-resistant prostate cancer, liquid biopsy, progression monitoring, therapy response},
pubstate = {published},
tppubtype = {article}
}
2023
Holme, Jørn A.; Vondráček, Jan; Machala, Miroslav; Lagadic-Gossmann, Dominique; Vogel, Christoph F. A.; Ferrec, Eric Le; Sparfel, Lydie; Øvrevik, Johan
In: Biochemical pharmacology, vol. 216, pp. 115801, 2023, ISSN: 1873-2968 0006-2952, (Place: England).
Abstract | Links | BibTeX | Tags: *Air Pollutants/toxicity, *Lung Neoplasms/chemically induced/genetics, *Polycyclic Aromatic Hydrocarbons/toxicity, Air pollution, Aryl Hydrocarbon/genetics, Carcinogenesis, Diesel exhaust, Environmental Monitoring, Genotoxicity, Humans, Inflammation, Occupational exposure, Particulate Matter/toxicity, Receptors, Smoking, Tumor metastasis, Tumor microenvironment, Tumor promotion
@article{holme_lung_2023,
title = {Lung cancer associated with combustion particles and fine particulate matter (PM(2.5)) - The roles of polycyclic aromatic hydrocarbons (PAHs) and the aryl hydrocarbon receptor (AhR).},
author = {Jørn A. Holme and Jan Vondráček and Miroslav Machala and Dominique Lagadic-Gossmann and Christoph F. A. Vogel and Eric Le Ferrec and Lydie Sparfel and Johan Øvrevik},
doi = {10.1016/j.bcp.2023.115801},
issn = {1873-2968 0006-2952},
year = {2023},
date = {2023-10-01},
journal = {Biochemical pharmacology},
volume = {216},
pages = {115801},
abstract = {Air pollution is the leading cause of lung cancer after tobacco smoking, contributing to 20% of all lung cancer deaths. Increased risk associated with living near trafficked roads, occupational exposure to diesel exhaust, indoor coal combustion and cigarette smoking, suggest that combustion components in ambient fine particulate matter (PM(2.5)), such as polycyclic aromatic hydrocarbons (PAHs), may be central drivers of lung cancer. Activation of the aryl hydrocarbon receptor (AhR) induces expression of xenobiotic-metabolizing enzymes (XMEs) and increase PAH metabolism, formation of reactive metabolites, oxidative stress, DNA damage and mutagenesis. Lung cancer tissues from smokers and workers exposed to high combustion PM levels contain mutagenic signatures derived from PAHs. However, recent findings suggest that ambient air PM(2.5) exposure primarily induces lung cancer development through tumor promotion of cells harboring naturally acquired oncogenic mutations, thus lacking typical PAH-induced mutations. On this background, we discuss the role of AhR and PAHs in lung cancer development caused by air pollution focusing on the tumor promoting properties including metabolism, immune system, cell proliferation and survival, tumor microenvironment, cell-to-cell communication, tumor growth and metastasis. We suggest that the dichotomy in lung cancer patterns observed between smoking and outdoor air PM(2.5) represent the two ends of a dose-response continuum of combustion PM exposure, where tumor promotion in the peripheral lung appears to be the driving factor at the relatively low-dose exposures from ambient air PM(2.5), whereas genotoxicity in the central airways becomes increasingly more important at the higher combustion PM levels encountered through smoking and occupational exposure.},
note = {Place: England},
keywords = {*Air Pollutants/toxicity, *Lung Neoplasms/chemically induced/genetics, *Polycyclic Aromatic Hydrocarbons/toxicity, Air pollution, Aryl Hydrocarbon/genetics, Carcinogenesis, Diesel exhaust, Environmental Monitoring, Genotoxicity, Humans, Inflammation, Occupational exposure, Particulate Matter/toxicity, Receptors, Smoking, Tumor metastasis, Tumor microenvironment, Tumor promotion},
pubstate = {published},
tppubtype = {article}
}
Vázquez-Gómez, Gerardo; Petráš, Jiří; Dvořák, Zdeněk; Vondráček, Jan
In: Biochemical pharmacology, vol. 216, pp. 115797, 2023, ISSN: 1873-2968 0006-2952, (Place: England).
Abstract | Links | BibTeX | Tags: *Receptors, Animals, Aryl hydrocarbon receptor, Aryl Hydrocarbon/genetics/metabolism, Carcinogenesis/genetics/metabolism, Colon cancer, Colon/metabolism, Dietary contaminants, Epithelial barrier, Inflammation, Inflammation/metabolism, Intestine, Mice, Microbial agonists, Pregnane X receptor, Pregnane X Receptor/metabolism, Steroid/metabolism
@article{vazquez-gomez_aryl_2023,
title = {Aryl hydrocarbon receptor (AhR) and pregnane X receptor (PXR) play both distinct and common roles in the regulation of colon homeostasis and intestinal carcinogenesis.},
author = {Gerardo Vázquez-Gómez and Jiří Petráš and Zdeněk Dvořák and Jan Vondráček},
doi = {10.1016/j.bcp.2023.115797},
issn = {1873-2968 0006-2952},
year = {2023},
date = {2023-10-01},
journal = {Biochemical pharmacology},
volume = {216},
pages = {115797},
abstract = {Both aryl hydrocarbon receptor (AhR) and pregnane X receptor (PXR) belong among key regulators of xenobiotic metabolism in the intestinal tissue. AhR in particular is activated by a wide range of environmental and dietary carcinogens. The data accumulated over the last two decades suggest that both of these transcriptional regulators play a much wider role in the maintenance of gut homeostasis, and that both transcription factors may affect processes linked with intestinal tumorigenesis. Intestinal epithelium is continuously exposed to a wide range of AhR, PXR and dual AhR/PXR ligands formed by intestinal microbiota or originating from diet. Current evidence suggests that specific ligands of both AhR and PXR can protect intestinal epithelium against inflammation and assist in the maintenance of epithelial barrier integrity. AhR, and to a lesser extent also PXR, have been shown to play a protective role against inflammation-induced colon cancer, or, in mouse models employing overactivation of Wnt/β-catenin signaling. In contrast, other evidence suggests that both receptors may contribute to modulation of transformed colon cell behavior, with a potential to promote cancer progression and/or chemoresistance. The review focuses on both overlapping and separate roles of the two receptors in these processes, and on possible implications of their activity within the context of intestinal tissue.},
note = {Place: England},
keywords = {*Receptors, Animals, Aryl hydrocarbon receptor, Aryl Hydrocarbon/genetics/metabolism, Carcinogenesis/genetics/metabolism, Colon cancer, Colon/metabolism, Dietary contaminants, Epithelial barrier, Inflammation, Inflammation/metabolism, Intestine, Mice, Microbial agonists, Pregnane X receptor, Pregnane X Receptor/metabolism, Steroid/metabolism},
pubstate = {published},
tppubtype = {article}
}
Sládeková, Lucia; Zgarbová, Eliška; Vrzal, Radim; Vanda, David; Soural, Miroslav; Jakubcová, Klára; Vázquez-Gómez, Gerardo; Vondráček, Jan; Dvořák, Zdeněk
Switching on/off aryl hydrocarbon receptor and pregnane X receptor activities by chemically modified tryptamines. Journal Article
In: Toxicology letters, vol. 387, pp. 63–75, 2023, ISSN: 1879-3169 0378-4274, (Place: Netherlands).
Abstract | Links | BibTeX | Tags: *Receptors, Aryl hydrocarbon receptor, Aryl Hydrocarbon/metabolism, Caco-2 Cells, Humans, Indoles/pharmacology, Microbial indoles, Pregnane X receptor, Pregnane X Receptor/genetics, Steroid/metabolism, Tryptamine, Tryptamines/pharmacology
@article{sladekova_switching_2023,
title = {Switching on/off aryl hydrocarbon receptor and pregnane X receptor activities by chemically modified tryptamines.},
author = {Lucia Sládeková and Eliška Zgarbová and Radim Vrzal and David Vanda and Miroslav Soural and Klára Jakubcová and Gerardo Vázquez-Gómez and Jan Vondráček and Zdeněk Dvořák},
doi = {10.1016/j.toxlet.2023.09.012},
issn = {1879-3169 0378-4274},
year = {2023},
date = {2023-09-01},
journal = {Toxicology letters},
volume = {387},
pages = {63–75},
abstract = {Microbial indoles have been demonstrated as selective or dual agonists and ligands of the pregnane X receptor (PXR) and aryl hydrocarbon receptor (AhR). However, structural determinants of microbial indoles selectivity towards both receptors remain elusive. Here, we studied the effects of existing and newly synthesized derivatives of indole microbial metabolite tryptamine on the activity of AhR and PXR receptors. We show that the elongation of indolyl-3-alkaneamine chain, indole N-methylation and conversion of indolyl-3-alkaneamines to oleamides resulted in a major increase of PXR activity and in parallel loss of AhR activity. Using reporter gene assays, RT-PCR and TR-FRET techniques, we have characterized in detail the activation of PXR by novel indolyl-3-alkanyl-oleamides, 1-methyltryptamine and 1-methyltryptamine-acetamide. As a proof of concept, we demonstrated anti-inflammatory and epithelial barrier-protective activity of lead derivatives in intestinal Caco-2 cells, employing the measurement of expression of pro-inflammatory chemokines, tight junction genes, trans-epithelial electric resistance TEER, and dextran-FITC permeability assay. In conclusion, we show that a subtle chemical modifications of simple microbial indole metabolite tryptamine, leads to substantial changes in AhR and PXR agonist activities.},
note = {Place: Netherlands},
keywords = {*Receptors, Aryl hydrocarbon receptor, Aryl Hydrocarbon/metabolism, Caco-2 Cells, Humans, Indoles/pharmacology, Microbial indoles, Pregnane X receptor, Pregnane X Receptor/genetics, Steroid/metabolism, Tryptamine, Tryptamines/pharmacology},
pubstate = {published},
tppubtype = {article}
}
Kahounová, Zuzana; Pícková, Markéta; Drápela, Stanislav; Bouchal, Jan; Szczyrbová, Eva; Navrátil, Jiří; Souček, Karel
Circulating tumor cell-derived preclinical models: current status and future perspectives. Journal Article
In: Cell death & disease, vol. 14, no. 8, pp. 530, 2023, ISSN: 2041-4889, (Place: England).
Abstract | Links | BibTeX | Tags: *Neoplastic Cells, Cell Culture Techniques, Circulating, Heterografts, Heterologous, Humans, Precision Medicine, Transplantation
@article{kahounova_circulating_2023,
title = {Circulating tumor cell-derived preclinical models: current status and future perspectives.},
author = {Zuzana Kahounová and Markéta Pícková and Stanislav Drápela and Jan Bouchal and Eva Szczyrbová and Jiří Navrátil and Karel Souček},
doi = {10.1038/s41419-023-06059-6},
issn = {2041-4889},
year = {2023},
date = {2023-08-01},
journal = {Cell death & disease},
volume = {14},
number = {8},
pages = {530},
abstract = {Despite the advancements made in the diagnosis and treatment of cancer, the stages associated with metastasis remain largely incurable and represent the primary cause of cancer-related deaths. The dissemination of cancer is facilitated by circulating tumor cells (CTCs), which originate from the primary tumor or metastatic sites and enter the bloodstream, subsequently spreading to distant parts of the body. CTCs have garnered significant attention in research due to their accessibility in peripheral blood, despite their low abundance. They are being extensively studied to gain a deeper understanding of the mechanisms underlying cancer dissemination and to identify effective therapeutic strategies for advanced stages of the disease. Therefore, substantial efforts have been directed towards establishing and characterizing relevant experimental models derived from CTCs, aiming to provide relevant tools for research. In this review, we provide an overview of recent progress in the establishment of preclinical CTC-derived models, such as CTC-derived xenografts (CDX) and cell cultures, which show promise for the study of CTCs. We discuss the advantages and limitations of these models and conclude by summarizing the potential future use of CTCs and CTC-derived models in cancer treatment decisions and their utility as precision medicine tools.},
note = {Place: England},
keywords = {*Neoplastic Cells, Cell Culture Techniques, Circulating, Heterografts, Heterologous, Humans, Precision Medicine, Transplantation},
pubstate = {published},
tppubtype = {article}
}
Marvanová, Soňa; Pěnčíková, Kateřina; Pálková, Lenka; Ciganek, Miroslav; Petráš, Jiří; Lněničková, Anna; Vondráček, Jan; Machala, Miroslav
Benzo[b]naphtho[d]thiophenes and naphthylbenzo[b]thiophenes: Their aryl hydrocarbon receptor-mediated activities and environmental presence. Journal Article
In: The Science of the total environment, vol. 879, pp. 162924, 2023, ISSN: 1879-1026 0048-9697, (Place: Netherlands).
Abstract | Links | BibTeX | Tags: *Environmental Pollutants, *Heterocyclic Compounds, AhR activity, Airborne particulate matter, Animals, Aryl Hydrocarbon, Freshwater sediments, Gap junctional intercellular communication, Humans, Particulate Matter, Polycyclic aromatic sulfur heterocyclic compounds, Rats, Receptors, Thiophenes/toxicity/metabolism
@article{marvanova_benzobnaphthodthiophenes_2023,
title = {Benzo[b]naphtho[d]thiophenes and naphthylbenzo[b]thiophenes: Their aryl hydrocarbon receptor-mediated activities and environmental presence.},
author = {Soňa Marvanová and Kateřina Pěnčíková and Lenka Pálková and Miroslav Ciganek and Jiří Petráš and Anna Lněničková and Jan Vondráček and Miroslav Machala},
doi = {10.1016/j.scitotenv.2023.162924},
issn = {1879-1026 0048-9697},
year = {2023},
date = {2023-06-01},
journal = {The Science of the total environment},
volume = {879},
pages = {162924},
abstract = {Polycyclic aromatic sulfur heterocyclic compounds (PASHs) belong among ubiquitous environmental pollutants; however, their toxic effects remain poorly understood. Here, we studied the aryl hydrocarbon receptor (AhR)-mediated activity of dibenzothiophene, benzo[b]naphtho[d]thiophenes, and naphthylbenzo[b]thiophenes, as well as their presence in two types of environmental matrices: river sediments collected from both rural and urban areas, and in airborne particulate matter (PM(2.5)) sampled in cities with different levels and sources of pollution. Benzo[b]naphtho[2,1-d]thiophene, benzo[b]naphtho[2,3-d]thiophene, 2,2-naphthylbenzo[b]thiophene, and 2,1-naphthylbenzo[b]thiophene were newly identified as efficient AhR agonists in both rat and human AhR-based reporter gene assays, with 2,2-naphthylbenzo[b]thiophene being the most potent compound identified in both species. Benzo[b]naphtho[1,2-d]thiophene and 3,2-naphthylbenzo[b]thiophene elicited AhR-mediated activity only in the rat liver cell model, while dibenzothiophene and 3,1-naphthylbenzo[b]thiophene were inactive in either cell type. Independently of their ability to activate the AhR, benzo[b]naphtho[1,2-d]thiophene, 2,1-naphthylbenzo[b]thiophene, 3,1-naphthylbenzo[b]thiophene, and 3,2-naphthylbenzo[b]thiophene inhibited gap junctional intercellular communication in a model of rat liver epithelial cells. Benzo[b]naphtho[d]thiophenes were dominant PASHs present in both PM(2.5) and sediment samples, with benzo[b]naphtho[2,1-d]thiophene being the most abundant one, followed by benzo[b]naphtho[2,3-d]thiophene. The levels of naphthylbenzo[b]thiophenes were mostly low or below detection limit. Benzo[b]naphtho[2,1-d]thiophene and benzo[b]naphtho[2,3-d]thiophene were identified as the most significant contributors to the AhR-mediated activity in the environmental samples evaluated in this study. Both induced nuclear translocation of the AhR, and they induced CYP1A1 expression in a time-dependent manner, suggesting that their AhR-mediated activity may depend on the rate of their intracellular metabolism. In conclusion, some PASHs could be significant contributors to the overall AhR-mediated toxicity of complex environmental samples suggesting that more attention should be paid to the potential health impacts of this group of environmental pollutants.},
note = {Place: Netherlands},
keywords = {*Environmental Pollutants, *Heterocyclic Compounds, AhR activity, Airborne particulate matter, Animals, Aryl Hydrocarbon, Freshwater sediments, Gap junctional intercellular communication, Humans, Particulate Matter, Polycyclic aromatic sulfur heterocyclic compounds, Rats, Receptors, Thiophenes/toxicity/metabolism},
pubstate = {published},
tppubtype = {article}
}
Kvokačková, Barbora; Fedr, Radek; Kužílková, Daniela; Stuchlý, Jan; Vávrová, Adéla; Navrátil, Jiří; Fabian, Pavel; Ondruššek, Róbert; Ovesná, Petra; Remšík, Ján; Bouchal, Jan; Kalina, Tomáš; Souček, Karel
Single-cell protein profiling defines cell populations associated with triple-negative breast cancer aggressiveness. Journal Article
In: Molecular oncology, vol. 17, no. 6, pp. 1024–1040, 2023, ISSN: 1878-0261 1574-7891, (Place: United States).
Abstract | Links | BibTeX | Tags: *Triple Negative Breast Neoplasms/metabolism, Cell Line, Humans, mass cytometry, phenotypic plasticity, Proteomics, Retrospective Studies, Signal Transduction, single-cell profiles, Stromal Cells/metabolism, triple-negative breast cancer, Tumor, tumor heterogeneity, Tumor microenvironment, unsupervised machine learning algorithm
@article{kvokackova_single-cell_2023,
title = {Single-cell protein profiling defines cell populations associated with triple-negative breast cancer aggressiveness.},
author = {Barbora Kvokačková and Radek Fedr and Daniela Kužílková and Jan Stuchlý and Adéla Vávrová and Jiří Navrátil and Pavel Fabian and Róbert Ondruššek and Petra Ovesná and Ján Remšík and Jan Bouchal and Tomáš Kalina and Karel Souček},
doi = {10.1002/1878-0261.13365},
issn = {1878-0261 1574-7891},
year = {2023},
date = {2023-06-01},
journal = {Molecular oncology},
volume = {17},
number = {6},
pages = {1024–1040},
abstract = {Triple-negative breast cancer (TNBC) is an aggressive and complex subtype of breast cancer that lacks targeted therapy. TNBC manifests characteristic, extensive intratumoral heterogeneity that promotes disease progression and influences drug response. Single-cell techniques in combination with next-generation computation provide an unprecedented opportunity to identify molecular events with therapeutic potential. Here, we describe the generation of a comprehensive mass cytometry panel for multiparametric detection of 23 phenotypic markers and 13 signaling molecules. This single-cell proteomic approach allowed us to explore the landscape of TNBC heterogeneity, with particular emphasis on the tumor microenvironment. We prospectively profiled freshly resected tumors from 26 TNBC patients. These tumors contained phenotypically distinct subpopulations of cancer and stromal cells that were associated with the patient's clinical status at the time of surgery. We further classified the epithelial-mesenchymal plasticity of tumor cells, and molecularly defined phenotypically diverse populations of tumor-associated stroma. Furthermore, in a retrospective tissue-microarray TNBC cohort, we showed that the level of CD97 at the time of surgery has prognostic potential.},
note = {Place: United States},
keywords = {*Triple Negative Breast Neoplasms/metabolism, Cell Line, Humans, mass cytometry, phenotypic plasticity, Proteomics, Retrospective Studies, Signal Transduction, single-cell profiles, Stromal Cells/metabolism, triple-negative breast cancer, Tumor, tumor heterogeneity, Tumor microenvironment, unsupervised machine learning algorithm},
pubstate = {published},
tppubtype = {article}
}
Fedr, Radek; Kahounová, Zuzana; Remšík, Ján; Reiterová, Michaela; Kalina, Tomáš; Souček, Karel
Variability of fluorescence intensity distribution measured by flow cytometry is influenced by cell size and cell cycle progression. Journal Article
In: Scientific reports, vol. 13, no. 1, pp. 4889, 2023, ISSN: 2045-2322, (Place: England).
Abstract | Links | BibTeX | Tags: *G2 Phase, Cell Cycle/physiology, Cell Division, Cell Size, Flow Cytometry/methods
@article{fedr_variability_2023,
title = {Variability of fluorescence intensity distribution measured by flow cytometry is influenced by cell size and cell cycle progression.},
author = {Radek Fedr and Zuzana Kahounová and Ján Remšík and Michaela Reiterová and Tomáš Kalina and Karel Souček},
doi = {10.1038/s41598-023-31990-1},
issn = {2045-2322},
year = {2023},
date = {2023-03-01},
journal = {Scientific reports},
volume = {13},
number = {1},
pages = {4889},
abstract = {The distribution of fluorescence signals measured with flow cytometry can be influenced by several factors, including qualitative and quantitative properties of the used fluorochromes, optical properties of the detection system, as well as the variability within the analyzed cell population itself. Most of the single cell samples prepared from in vitrocultures or clinical specimens contain a variable cell cycle component. Cell cycle, together with changes in the cell size, are two of the factors that alter the functional properties of analyzed cells and thus affect the interpretation of obtained results. Here, we describe the association between cell cycle status and cell size, and the variability in the distribution of fluorescence intensity as determined with flow cytometry, at population scale. We show that variability in the distribution of background and specific fluorescence signals is related to the cell cycle state of the selected population, with the 10% low fluorescence signal fraction enriched mainly in cells in their G0/G1 cell cycle phase, and the 10% high fraction containing cells mostly in the G2/M phase. Therefore we advise using caution and additional experimental validation when comparing populations defined by fractions at both ends of fluorescence signal distribution to avoid biases caused by the effect of cell cycle and cell size.},
note = {Place: England},
keywords = {*G2 Phase, Cell Cycle/physiology, Cell Division, Cell Size, Flow Cytometry/methods},
pubstate = {published},
tppubtype = {article}
}
Culig, Zoran; Jolly, Mohit Kumar; Souček, Karel
Editorial: Heterogeneity and plasticity of prostate cancer. Journal Article
In: Frontiers in molecular biosciences, vol. 10, pp. 1228126, 2023, ISSN: 2296-889X, (Place: Switzerland).
Links | BibTeX | Tags: heterogeneity, immunotherapy, oncogenic miRNA, Plasticity, Prostate cancer, therapy resistance, Transcription Factors, tumor-suppressive miRNA
@article{culig_editorial_2023,
title = {Editorial: Heterogeneity and plasticity of prostate cancer.},
author = {Zoran Culig and Mohit Kumar Jolly and Karel Souček},
doi = {10.3389/fmolb.2023.1228126},
issn = {2296-889X},
year = {2023},
date = {2023-01-01},
journal = {Frontiers in molecular biosciences},
volume = {10},
pages = {1228126},
note = {Place: Switzerland},
keywords = {heterogeneity, immunotherapy, oncogenic miRNA, Plasticity, Prostate cancer, therapy resistance, Transcription Factors, tumor-suppressive miRNA},
pubstate = {published},
tppubtype = {article}
}
Ondruššek, Róbert; Kvokačková, Barbora; Kryštofová, Karolína; Brychtová, Světlana; Souček, Karel; Bouchal, Jan
Prognostic value and multifaceted roles of tetraspanin CD9 in cancer. Journal Article
In: Frontiers in oncology, vol. 13, pp. 1140738, 2023, ISSN: 2234-943X, (Place: Switzerland).
Abstract | Links | BibTeX | Tags: cancer, CD9, exosomes, Immunohistochemistry, Prognosis
@article{ondrussek_prognostic_2023,
title = {Prognostic value and multifaceted roles of tetraspanin CD9 in cancer.},
author = {Róbert Ondruššek and Barbora Kvokačková and Karolína Kryštofová and Světlana Brychtová and Karel Souček and Jan Bouchal},
doi = {10.3389/fonc.2023.1140738},
issn = {2234-943X},
year = {2023},
date = {2023-01-01},
journal = {Frontiers in oncology},
volume = {13},
pages = {1140738},
abstract = {CD9 is a crucial regulator of cell adhesion in the immune system and plays important physiological roles in hematopoiesis, blood coagulation or viral and bacterial infections. It is involved in the transendothelial migration of leukocytes which might also be hijacked by cancer cells during their invasion and metastasis. CD9 is found at the cell surface and the membrane of exosomes affecting cancer progression and therapy resistance. High expression of CD9 is mostly associated with good patients outcome, with a few exceptions. Discordant findings have been reported for breast, ovarian, melanoma, pancreatic and esophageal cancer, which might be related to using different antibodies or inherent cancer heterogeneity. According to in vitro and in vivo studies, tetraspanin CD9 is not clearly associated with either tumor suppression or promotion. Further mechanistic experiments will elucidate the role of CD9 in particular cancer types and specific conditions.},
note = {Place: Switzerland},
keywords = {cancer, CD9, exosomes, Immunohistochemistry, Prognosis},
pubstate = {published},
tppubtype = {article}
}
2022
Bernal, Kévin; Touma, Charbel; Erradhouani, Chedi; Boronat-Belda, Talía; Gaillard, Lucas; Kassir, Sara Al; Mentec, Hélène Le; Martin-Chouly, Corinne; Podechard, Normand; Lagadic-Gossmann, Dominique; Langouet, Sophie; Brion, François; Knoll-Gellida, Anja; Babin, Patrick J.; Sovadinova, Iva; Babica, Pavel; Andreau, Karine; Barouki, Robert; Vondracek, Jan; Alonso-Magdalena, Paloma; Blanc, Etienne; Kim, Min Ji; Coumoul, Xavier
Combinatorial pathway disruption is a powerful approach to delineate metabolic impacts of endocrine disruptors. Journal Article
In: FEBS letters, vol. 596, no. 24, pp. 3107–3123, 2022, ISSN: 1873-3468 0014-5793, (Place: England).
Abstract | Links | BibTeX | Tags: *Endocrine Disruptors/toxicity, *Metabolic Syndrome, appetite, bisphenol, dioxin, Humans, Inflammation, insulin resistance, microbiota, Obesity/chemically induced, perfluorinated compounds, Phenols, phthalate, TBT
@article{bernal_combinatorial_2022,
title = {Combinatorial pathway disruption is a powerful approach to delineate metabolic impacts of endocrine disruptors.},
author = {Kévin Bernal and Charbel Touma and Chedi Erradhouani and Talía Boronat-Belda and Lucas Gaillard and Sara Al Kassir and Hélène Le Mentec and Corinne Martin-Chouly and Normand Podechard and Dominique Lagadic-Gossmann and Sophie Langouet and François Brion and Anja Knoll-Gellida and Patrick J. Babin and Iva Sovadinova and Pavel Babica and Karine Andreau and Robert Barouki and Jan Vondracek and Paloma Alonso-Magdalena and Etienne Blanc and Min Ji Kim and Xavier Coumoul},
doi = {10.1002/1873-3468.14465},
issn = {1873-3468 0014-5793},
year = {2022},
date = {2022-12-01},
journal = {FEBS letters},
volume = {596},
number = {24},
pages = {3107–3123},
abstract = {The prevalence of metabolic diseases, such as obesity, diabetes, metabolic syndrome and chronic liver diseases among others, has been rising for several years. Epidemiology and mechanistic (in vivo, in vitro and in silico) toxicology have recently provided compelling evidence implicating the chemical environment in the pathogenesis of these diseases. In this review, we will describe the biological processes that contribute to the development of metabolic diseases targeted by metabolic disruptors, and will propose an integrated pathophysiological vision of their effects on several organs. With regard to these pathomechanisms, we will discuss the needs, and the stakes of evolving the testing and assessment of endocrine disruptors to improve the prevention and management of metabolic diseases that have become a global epidemic since the end of last century.},
note = {Place: England},
keywords = {*Endocrine Disruptors/toxicity, *Metabolic Syndrome, appetite, bisphenol, dioxin, Humans, Inflammation, insulin resistance, microbiota, Obesity/chemically induced, perfluorinated compounds, Phenols, phthalate, TBT},
pubstate = {published},
tppubtype = {article}
}
Kotasová, Hana; Capandová, Michaela; Pelková, Vendula; Dumková, Jana; Koledová, Zuzana; Remšík, Ján; Souček, Karel; Garlíková, Zuzana; Sedláková, Veronika; Rabata, Anas; Vaňhara, Petr; Moráň, Lukáš; Pečinka, Lukáš; Porokh, Volodymyr; Kučírek, Martin; Streit, Libor; Havel, Josef; Hampl, Aleš
Expandable Lung Epithelium Differentiated from Human Embryonic Stem Cells. Journal Article
In: Tissue engineering and regenerative medicine, vol. 19, no. 5, pp. 1033–1050, 2022, ISSN: 2212-5469 1738-2696, (Place: Korea (South)).
Abstract | Links | BibTeX | Tags: *Human Embryonic Stem Cells, Cell Differentiation, Differentiation, Epithelium, Foregut endoderm, hESC, Humans, Lung, Lung/metabolism, Surface-Active Agents/metabolism
@article{kotasova_expandable_2022,
title = {Expandable Lung Epithelium Differentiated from Human Embryonic Stem Cells.},
author = {Hana Kotasová and Michaela Capandová and Vendula Pelková and Jana Dumková and Zuzana Koledová and Ján Remšík and Karel Souček and Zuzana Garlíková and Veronika Sedláková and Anas Rabata and Petr Vaňhara and Lukáš Moráň and Lukáš Pečinka and Volodymyr Porokh and Martin Kučírek and Libor Streit and Josef Havel and Aleš Hampl},
doi = {10.1007/s13770-022-00458-0},
issn = {2212-5469 1738-2696},
year = {2022},
date = {2022-10-01},
journal = {Tissue engineering and regenerative medicine},
volume = {19},
number = {5},
pages = {1033–1050},
abstract = {BACKGROUND: The progenitors to lung airway epithelium that are capable of long-term propagation may represent an attractive source of cells for cell-based therapies, disease modeling, toxicity testing, and others. Principally, there are two main options for obtaining lung epithelial progenitors: (i) direct isolation of endogenous progenitors from human lungs and (ii) in vitro differentiation from some other cell type. The prime candidates for the second approach are pluripotent stem cells, which may provide autologous and/or allogeneic cell resource in clinically relevant quality and quantity. METHODS: By exploiting the differentiation potential of human embryonic stem cells (hESC), here we derived expandable lung epithelium (ELEP) and established culture conditions for their long-term propagation (more than 6 months) in a monolayer culture without a need of 3D culture conditions and/or cell sorting steps, which minimizes potential variability of the outcome. RESULTS: These hESC-derived ELEP express NK2 Homeobox 1 (NKX2.1), a marker of early lung epithelial lineage, display properties of cells in early stages of surfactant production and are able to differentiate to cells exhibitting molecular and morphological characteristics of both respiratory epithelium of airway and alveolar regions. CONCLUSION: Expandable lung epithelium thus offer a stable, convenient, easily scalable and high-yielding cell source for applications in biomedicine.},
note = {Place: Korea (South)},
keywords = {*Human Embryonic Stem Cells, Cell Differentiation, Differentiation, Epithelium, Foregut endoderm, hESC, Humans, Lung, Lung/metabolism, Surface-Active Agents/metabolism},
pubstate = {published},
tppubtype = {article}
}
Muresan, Ximena M.; Slabáková, Eva; Procházková, Jiřina; Drápela, Stanislav; Fedr, Radek; Pícková, Markéta; Vacek, Ondřej; Víchová, Ráchel; Suchánková, Tereza; Bouchal, Jan; Kürfürstová, Daniela; Král, Milan; Hulínová, Tereza; Sýkora, Radek P.; Študent, Vladimír; Hejret, Václav; Weerden, Wytske M.; Puhr, Martin; Pustka, Václav; Potěšil, David; Zdráhal, Zbyněk; Culig, Zoran; Souček, Karel
Toll-Like Receptor 3 Overexpression Induces Invasion of Prostate Cancer Cells, whereas Its Activation Triggers Apoptosis. Journal Article
In: The American journal of pathology, vol. 192, no. 9, pp. 1321–1335, 2022, ISSN: 1525-2191 0002-9440, (Place: United States).
Abstract | Links | BibTeX | Tags: *Prostatic Neoplasms/pathology, *Toll-Like Receptor 3/genetics/metabolism, Animals, Apoptosis, Cell Line, Humans, Male, Poly I-C/pharmacology, Prostate/pathology, Tumor
@article{muresan_toll-like_2022,
title = {Toll-Like Receptor 3 Overexpression Induces Invasion of Prostate Cancer Cells, whereas Its Activation Triggers Apoptosis.},
author = {Ximena M. Muresan and Eva Slabáková and Jiřina Procházková and Stanislav Drápela and Radek Fedr and Markéta Pícková and Ondřej Vacek and Ráchel Víchová and Tereza Suchánková and Jan Bouchal and Daniela Kürfürstová and Milan Král and Tereza Hulínová and Radek P. Sýkora and Vladimír Študent and Václav Hejret and Wytske M. Weerden and Martin Puhr and Václav Pustka and David Potěšil and Zbyněk Zdráhal and Zoran Culig and Karel Souček},
doi = {10.1016/j.ajpath.2022.05.009},
issn = {1525-2191 0002-9440},
year = {2022},
date = {2022-09-01},
journal = {The American journal of pathology},
volume = {192},
number = {9},
pages = {1321–1335},
abstract = {Toll-like receptor 3 (TLR3) is an endosomal receptor expressed in several immune and epithelial cells. Recent studies have highlighted its expression also in solid tumors, including prostate cancer (PCa), and have described its role primarily in the proinflammatory response and induction of apoptosis. It is up-regulated in some castration-resistant prostate cancers. However, the role of TLR3 in prostate cancer progression remains largely unknown. The current study experimentally demonstrated that exogenous TLR3 activation in PCa cell lines leads to a significant induction of secretion of the cytokines IL-6, IL-8, and interferon-β, depending on the model and chemoresistance status. Transcriptomic analysis of TLR3-overexpressing cells revealed a functional program that is enriched for genes involved in the regulation of cell motility, migration, and tumor invasiveness. Increased motility, migration, and invasion in TLR3-overexpressing cell line were confirmed by several in vitro assays and using an orthotopic prostate xenograft model in vivo. Furthermore, TLR3-ligand induced apoptosis via cleavage of caspase-3/7 and poly (ADP-ribose) polymerase, predominantly in TLR3-overexpressing cells. These results indicate that TLR3 may be involved in prostate cancer progression and metastasis; however, it might also represent an Achilles heel of PCa, which can be exploited for targeted therapy.},
note = {Place: United States},
keywords = {*Prostatic Neoplasms/pathology, *Toll-Like Receptor 3/genetics/metabolism, Animals, Apoptosis, Cell Line, Humans, Male, Poly I-C/pharmacology, Prostate/pathology, Tumor},
pubstate = {published},
tppubtype = {article}
}
Karasová, Martina; Procházková, Jiřina; Tylichová, Zuzana; Fedr, Radek; Ciganek, Miroslav; Machala, Miroslav; Dvořák, Zdeněk; Vyhlídalová, Barbora; Zůvalová, Iveta; Ehrmann, Jiří; Bouchal, Jan; Andrysík, Zdeněk; Vondráček, Jan
In: Cancers, vol. 14, no. 17, 2022, ISSN: 2072-6694, (Place: Switzerland).
Abstract | Links | BibTeX | Tags: AhR, Akt pathway, colon cancer cells, fatty acid synthesis, metabolism, proliferation
@article{karasova_inhibition_2022,
title = {Inhibition of Aryl Hydrocarbon Receptor (AhR) Expression Disrupts Cell Proliferation and Alters Energy Metabolism and Fatty Acid Synthesis in Colon Cancer Cells.},
author = {Martina Karasová and Jiřina Procházková and Zuzana Tylichová and Radek Fedr and Miroslav Ciganek and Miroslav Machala and Zdeněk Dvořák and Barbora Vyhlídalová and Iveta Zůvalová and Jiří Ehrmann and Jan Bouchal and Zdeněk Andrysík and Jan Vondráček},
doi = {10.3390/cancers14174245},
issn = {2072-6694},
year = {2022},
date = {2022-08-01},
journal = {Cancers},
volume = {14},
number = {17},
abstract = {The aryl hydrocarbon receptor (AhR) plays a wide range of physiological roles in cellular processes such as proliferation, migration or control of immune responses. Several studies have also indicated that AhR might contribute to the regulation of energy balance or cellular metabolism. We observed that the AhR is upregulated in tumor epithelial cells derived from colon cancer patients. Using wild-type and the corresponding AhR knockout (AhR KO) variants of human colon cancer cell lines HCT116 and HT-29, we analyzed possible role(s) of the AhR in cell proliferation and metabolism, with a focus on regulation of the synthesis of fatty acids (FAs). We observed a decreased proliferation rate in the AhR KO cells, which was accompanied with altered cell cycle progression, as well as a decreased ATP production. We also found reduced mRNA levels of key enzymes of the FA biosynthetic pathway in AhR KO colon cancer cells, in particular of stearoyl-CoA desaturase 1 (SCD1). The loss of AhR was also associated with reduced expression and/or activity of components of the PI3K/Akt pathway, which controls lipid metabolism, and other lipogenic transcriptional regulators, such as sterol regulatory element binding transcription factor 1 (SREBP1). Together, our data indicate that disruption of AhR activity in colon tumor cells may, likely in a cell-specific manner, limit their proliferation, which could be linked with a suppressive effect on their endogenous FA metabolism. More attention should be paid to potential mechanistic links between overexpressed AhR and colon tumor cell metabolism.},
note = {Place: Switzerland},
keywords = {AhR, Akt pathway, colon cancer cells, fatty acid synthesis, metabolism, proliferation},
pubstate = {published},
tppubtype = {article}
}
Smutná, Tereza; Dumková, Jana; Kristeková, Daniela; Laštovičková, Markéta; Jedličková, Adriena; Vrlíková, Lucie; Dočekal, Bohumil; Alexa, Lukáš; Kotasová, Hana; Pelková, Vendula; Večeřa, Zbyněk; Křůmal, Kamil; Petráš, Jiří; Coufalík, Pavel; Všianský, Dalibor; Záchej, Samuel; Pinkas, Dominik; Vondráček, Jan; Hampl, Aleš; Mikuška, Pavel; Buchtová, Marcela
In: Particle and fibre toxicology, vol. 19, no. 1, pp. 52, 2022, ISSN: 1743-8977, (Place: England).
Abstract | Links | BibTeX | Tags: *Metal Nanoparticles/chemistry, *Type C Phospholipases, Cholesterol, Cholesterol metabolism, Humans, Inflammation, Inhalation, Lead, Lead oxide nanoparticles, Liver macrophages, Lung macrophages, Macrophages, Oxides
@article{smutna_macrophage-mediated_2022,
title = {Macrophage-mediated tissue response evoked by subchronic inhalation of lead oxide nanoparticles is associated with the alteration of phospholipases C and cholesterol transporters.},
author = {Tereza Smutná and Jana Dumková and Daniela Kristeková and Markéta Laštovičková and Adriena Jedličková and Lucie Vrlíková and Bohumil Dočekal and Lukáš Alexa and Hana Kotasová and Vendula Pelková and Zbyněk Večeřa and Kamil Křůmal and Jiří Petráš and Pavel Coufalík and Dalibor Všianský and Samuel Záchej and Dominik Pinkas and Jan Vondráček and Aleš Hampl and Pavel Mikuška and Marcela Buchtová},
doi = {10.1186/s12989-022-00494-7},
issn = {1743-8977},
year = {2022},
date = {2022-08-01},
journal = {Particle and fibre toxicology},
volume = {19},
number = {1},
pages = {52},
abstract = {BACKGROUND: Inhalation of lead oxide nanoparticles (PbO NPs), which are emitted to the environment by high-temperature technological processes, heavily impairs target organs. These nanoparticles pass through the lung barrier and are distributed via the blood into secondary target organs, where they cause numerous pathological alterations. Here, we studied in detail, macrophages as specialized cells involved in the innate and adaptive immune response in selected target organs to unravel their potential involvement in reaction to subchronic PbO NP inhalation. In this context, we also tackled possible alterations in lipid uptake in the lungs and liver, which is usually associated with foam macrophage formation. RESULTS: The histopathological analysis of PbO NP exposed lung revealed serious chronic inflammation of lung tissues. The number of total and foam macrophages was significantly increased in lung, and they contained numerous cholesterol crystals. PbO NP inhalation induced changes in expression of phospholipases C (PLC) as enzymes linked to macrophage-mediated inflammation in lungs. In the liver, the subchronic inhalation of PbO NPs caused predominantly hyperemia, microsteatosis or remodeling of the liver parenchyma, and the number of liver macrophages also significantly was increased. The gene and protein expression of a cholesterol transporter CD36, which is associated with lipid metabolism, was altered in the liver. The amount of selected cholesteryl esters (CE 16:0, CE 18:1, CE 20:4, CE 22:6) in liver tissue was decreased after subchronic PbO NP inhalation, while total and free cholesterol in liver tissue was slightly increased. Gene and protein expression of phospholipase PLCβ1 and receptor CD36 in human hepatocytes were affected also in in vitro experiments after acute PbO NP exposure. No microscopic or serious functional kidney alterations were detected after subchronic PbO NP exposure and CD68 positive cells were present in the physiological mode in its interstitial tissues. CONCLUSION: Our study revealed the association of increased cholesterol and lipid storage in targeted tissues with the alteration of scavenger receptors and phospholipases C after subchronic inhalation of PbO NPs and yet uncovered processes, which can contribute to steatosis in liver after metal nanoparticles exposure.},
note = {Place: England},
keywords = {*Metal Nanoparticles/chemistry, *Type C Phospholipases, Cholesterol, Cholesterol metabolism, Humans, Inflammation, Inhalation, Lead, Lead oxide nanoparticles, Liver macrophages, Lung macrophages, Macrophages, Oxides},
pubstate = {published},
tppubtype = {article}
}
Heindel, Jerrold J.; Howard, Sarah; Agay-Shay, Keren; Arrebola, Juan P.; Audouze, Karine; Babin, Patrick J.; Barouki, Robert; Bansal, Amita; Blanc, Etienne; Cave, Matthew C.; Chatterjee, Saurabh; Chevalier, Nicolas; Choudhury, Mahua; Collier, David; Connolly, Lisa; Coumoul, Xavier; Garruti, Gabriella; Gilbertson, Michael; Hoepner, Lori A.; Holloway, Alison C.; 3rd Howell, George; Kassotis, Christopher D.; Kay, Mathew K.; Kim, Min Ji; Lagadic-Gossmann, Dominique; Langouet, Sophie; Legrand, Antoine; Li, Zhuorui; Mentec, Helene Le; Lind, Lars; Lind, P. Monica; Lustig, Robert H.; Martin-Chouly, Corinne; Kos, Vesna Munic; Podechard, Normand; Roepke, Troy A.; Sargis, Robert M.; Starling, Anne; Tomlinson, Craig R.; Touma, Charbel; Vondracek, Jan; Saal, Frederick Vom; Blumberg, Bruce
Corrigendum to "Obesity II: Establishing causal links between chemical exposures and obesity" [Biochem. Pharmacol. 199 (2022) 115015]. Journal Article
In: Biochemical pharmacology, vol. 202, pp. 115144, 2022, ISSN: 1873-2968 0006-2952, (Place: England).
@article{heindel_corrigendum_2022,
title = {Corrigendum to "Obesity II: Establishing causal links between chemical exposures and obesity" [Biochem. Pharmacol. 199 (2022) 115015].},
author = {Jerrold J. Heindel and Sarah Howard and Keren Agay-Shay and Juan P. Arrebola and Karine Audouze and Patrick J. Babin and Robert Barouki and Amita Bansal and Etienne Blanc and Matthew C. Cave and Saurabh Chatterjee and Nicolas Chevalier and Mahua Choudhury and David Collier and Lisa Connolly and Xavier Coumoul and Gabriella Garruti and Michael Gilbertson and Lori A. Hoepner and Alison C. Holloway and George 3rd Howell and Christopher D. Kassotis and Mathew K. Kay and Min Ji Kim and Dominique Lagadic-Gossmann and Sophie Langouet and Antoine Legrand and Zhuorui Li and Helene Le Mentec and Lars Lind and P. Monica Lind and Robert H. Lustig and Corinne Martin-Chouly and Vesna Munic Kos and Normand Podechard and Troy A. Roepke and Robert M. Sargis and Anne Starling and Craig R. Tomlinson and Charbel Touma and Jan Vondracek and Frederick Vom Saal and Bruce Blumberg},
doi = {10.1016/j.bcp.2022.115144},
issn = {1873-2968 0006-2952},
year = {2022},
date = {2022-08-01},
journal = {Biochemical pharmacology},
volume = {202},
pages = {115144},
note = {Place: England},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Lenárt, Sára; Lenárt, Peter; Knopfová, Lucia; Kotasová, Hana; Pelková, Vendula; Sedláková, Veronika; Vacek, Ondřej; Pokludová, Jana; Čan, Vladimír; Šmarda, Jan; Souček, Karel; Hampl, Aleš; Beneš, Petr
TACSTD2 upregulation is an early reaction to lung infection. Journal Article
In: Scientific reports, vol. 12, no. 1, pp. 9583, 2022, ISSN: 2045-2322, (Place: England).
Abstract | Links | BibTeX | Tags: *Antigens, *Cell Adhesion Molecules/metabolism, Animals, Epithelial Cells/metabolism, Lung/metabolism, Neoplasm/metabolism, Up-Regulation
@article{lenart_tacstd2_2022,
title = {TACSTD2 upregulation is an early reaction to lung infection.},
author = {Sára Lenárt and Peter Lenárt and Lucia Knopfová and Hana Kotasová and Vendula Pelková and Veronika Sedláková and Ondřej Vacek and Jana Pokludová and Vladimír Čan and Jan Šmarda and Karel Souček and Aleš Hampl and Petr Beneš},
doi = {10.1038/s41598-022-13637-9},
issn = {2045-2322},
year = {2022},
date = {2022-06-01},
journal = {Scientific reports},
volume = {12},
number = {1},
pages = {9583},
abstract = {TACSTD2 encodes a transmembrane glycoprotein Trop2 commonly overexpressed in carcinomas. While the Trop2 protein was discovered already in 1981 and first antibody-drug conjugate targeting Trop2 were recently approved for cancer therapy, the physiological role of Trop2 is still not fully understood. In this article, we show that TACSTD2/Trop2 expression is evolutionarily conserved in lungs of various vertebrates. By analysis of publicly available transcriptomic data we demonstrate that TACSTD2 level consistently increases in lungs infected with miscellaneous, but mainly viral pathogens. Single cell and subpopulation based transcriptomic data revealed that the major source of TACSTD2 transcript are lung epithelial cells and their progenitors and that TACSTD2 is induced directly in lung epithelial cells following infection. Increase in TACSTD2 expression may represent a mechanism to maintain/restore epithelial barrier function and contribute to regeneration process in infected/damaged lungs.},
note = {Place: England},
keywords = {*Antigens, *Cell Adhesion Molecules/metabolism, Animals, Epithelial Cells/metabolism, Lung/metabolism, Neoplasm/metabolism, Up-Regulation},
pubstate = {published},
tppubtype = {article}
}
Heindel, Jerrold J.; Howard, Sarah; Agay-Shay, Keren; Arrebola, Juan P.; Audouze, Karine; Babin, Patrick J.; Barouki, Robert; Bansal, Amita; Blanc, Etienne; Cave, Matthew C.; Chatterjee, Saurabh; Chevalier, Nicolas; Choudhury, Mahua; Collier, David; Connolly, Lisa; Coumoul, Xavier; Garruti, Gabriella; Gilbertson, Michael; Hoepner, Lori A.; Holloway, Alison C.; 3rd Howell, George; Kassotis, Christopher D.; Kay, Mathew K.; Kim, Min Ji; Lagadic-Gossmann, Dominique; Langouet, Sophie; Legrand, Antoine; Li, Zhuorui; Mentec, Helene Le; Lind, Lars; Lind, P. Monica; Lustig, Robert H.; Martin-Chouly, Corinne; Kos, Vesna Munic; Podechard, Normand; Roepke, Troy A.; Sargis, Robert M.; Starling, Anne; Tomlinson, Craig R.; Touma, Charbel; Vondracek, Jan; Saal, Frederick Vom; Blumberg, Bruce
Obesity II: Establishing causal links between chemical exposures and obesity. Journal Article
In: Biochemical pharmacology, vol. 199, pp. 115015, 2022, ISSN: 1873-2968 0006-2952, (Place: England).
Abstract | Links | BibTeX | Tags: *Endocrine Disruptors/toxicity, Adipocyte differentiation, Adipogenesis, Adipose Tissue, Child, Endocrine disruptor, Environmental Exposure/adverse effects, Humans, Obesity, Obesity/etiology, Obesogen, Preschool, Weight Gain
@article{heindel_obesity_2022,
title = {Obesity II: Establishing causal links between chemical exposures and obesity.},
author = {Jerrold J. Heindel and Sarah Howard and Keren Agay-Shay and Juan P. Arrebola and Karine Audouze and Patrick J. Babin and Robert Barouki and Amita Bansal and Etienne Blanc and Matthew C. Cave and Saurabh Chatterjee and Nicolas Chevalier and Mahua Choudhury and David Collier and Lisa Connolly and Xavier Coumoul and Gabriella Garruti and Michael Gilbertson and Lori A. Hoepner and Alison C. Holloway and George 3rd Howell and Christopher D. Kassotis and Mathew K. Kay and Min Ji Kim and Dominique Lagadic-Gossmann and Sophie Langouet and Antoine Legrand and Zhuorui Li and Helene Le Mentec and Lars Lind and P. Monica Lind and Robert H. Lustig and Corinne Martin-Chouly and Vesna Munic Kos and Normand Podechard and Troy A. Roepke and Robert M. Sargis and Anne Starling and Craig R. Tomlinson and Charbel Touma and Jan Vondracek and Frederick Vom Saal and Bruce Blumberg},
doi = {10.1016/j.bcp.2022.115015},
issn = {1873-2968 0006-2952},
year = {2022},
date = {2022-05-01},
journal = {Biochemical pharmacology},
volume = {199},
pages = {115015},
abstract = {Obesity is a multifactorial disease with both genetic and environmental components. The prevailing view is that obesity results from an imbalance between energy intake and expenditure caused by overeating and insufficient exercise. We describe another environmental element that can alter the balance between energy intake and energy expenditure: obesogens. Obesogens are a subset of environmental chemicals that act as endocrine disruptors affecting metabolic endpoints. The obesogen hypothesis posits that exposure to endocrine disruptors and other chemicals can alter the development and function of the adipose tissue, liver, pancreas, gastrointestinal tract, and brain, thus changing the set point for control of metabolism. Obesogens can determine how much food is needed to maintain homeostasis and thereby increase the susceptibility to obesity. The most sensitive time for obesogen action is in utero and early childhood, in part via epigenetic programming that can be transmitted to future generations. This review explores the evidence supporting the obesogen hypothesis and highlights knowledge gaps that have prevented widespread acceptance as a contributor to the obesity pandemic. Critically, the obesogen hypothesis changes the narrative from curing obesity to preventing obesity.},
note = {Place: England},
keywords = {*Endocrine Disruptors/toxicity, Adipocyte differentiation, Adipogenesis, Adipose Tissue, Child, Endocrine disruptor, Environmental Exposure/adverse effects, Humans, Obesity, Obesity/etiology, Obesogen, Preschool, Weight Gain},
pubstate = {published},
tppubtype = {article}
}
Lustig, Robert H.; Collier, David; Kassotis, Christopher; Roepke, Troy A.; Kim, Min Ji; Blanc, Etienne; Barouki, Robert; Bansal, Amita; Cave, Matthew C.; Chatterjee, Saurabh; Choudhury, Mahua; Gilbertson, Michael; Lagadic-Gossmann, Dominique; Howard, Sarah; Lind, Lars; Tomlinson, Craig R.; Vondracek, Jan; Heindel, Jerrold J.
Obesity I: Overview and molecular and biochemical mechanisms. Journal Article
In: Biochemical pharmacology, vol. 199, pp. 115012, 2022, ISSN: 1873-2968 0006-2952, (Place: England).
Abstract | Links | BibTeX | Tags: *Leptin/metabolism, *Obesity/metabolism, Adipocytes/metabolism, Adipose Tissue, Adipose Tissue/metabolism, Energy balance, Energy Metabolism/physiology, Hormone receptors, Humans, Insulin/metabolism, metabolism, Microbiome, Obesity
@article{lustig_obesity_2022,
title = {Obesity I: Overview and molecular and biochemical mechanisms.},
author = {Robert H. Lustig and David Collier and Christopher Kassotis and Troy A. Roepke and Min Ji Kim and Etienne Blanc and Robert Barouki and Amita Bansal and Matthew C. Cave and Saurabh Chatterjee and Mahua Choudhury and Michael Gilbertson and Dominique Lagadic-Gossmann and Sarah Howard and Lars Lind and Craig R. Tomlinson and Jan Vondracek and Jerrold J. Heindel},
doi = {10.1016/j.bcp.2022.115012},
issn = {1873-2968 0006-2952},
year = {2022},
date = {2022-05-01},
journal = {Biochemical pharmacology},
volume = {199},
pages = {115012},
abstract = {Obesity is a chronic, relapsing condition characterized by excess body fat. Its prevalence has increased globally since the 1970s, and the number of obese and overweight people is now greater than those underweight. Obesity is a multifactorial condition, and as such, many components contribute to its development and pathogenesis. This is the first of three companion reviews that consider obesity. This review focuses on the genetics, viruses, insulin resistance, inflammation, gut microbiome, and circadian rhythms that promote obesity, along with hormones, growth factors, and organs and tissues that control its development. It shows that the regulation of energy balance (intake vs. expenditure) relies on the interplay of a variety of hormones from adipose tissue, gastrointestinal tract, pancreas, liver, and brain. It details how integrating central neurotransmitters and peripheral metabolic signals (e.g., leptin, insulin, ghrelin, peptide YY(3-36)) is essential for controlling energy homeostasis and feeding behavior. It describes the distinct types of adipocytes and how fat cell development is controlled by hormones and growth factors acting via a variety of receptors, including peroxisome proliferator-activated receptor-gamma, retinoid X, insulin, estrogen, androgen, glucocorticoid, thyroid hormone, liver X, constitutive androstane, pregnane X, farnesoid, and aryl hydrocarbon receptors. Finally, it demonstrates that obesity likely has origins in utero. Understanding these biochemical drivers of adiposity and metabolic dysfunction throughout the life cycle lends plausibility and credence to the "obesogen hypothesis" (i.e., the importance of environmental chemicals that disrupt these receptors to promote adiposity or alter metabolism), elucidated more fully in the two companion reviews.},
note = {Place: England},
keywords = {*Leptin/metabolism, *Obesity/metabolism, Adipocytes/metabolism, Adipose Tissue, Adipose Tissue/metabolism, Energy balance, Energy Metabolism/physiology, Hormone receptors, Humans, Insulin/metabolism, metabolism, Microbiome, Obesity},
pubstate = {published},
tppubtype = {article}
}
Říhová, Kamila; Dúcka, Monika; Zambo, Iva Staniczková; Vymětalová, Ladislava; Šrámek, Martin; Trčka, Filip; Verner, Jan; Drápela, Stanislav; Fedr, Radek; Suchánková, Tereza; Pavlatovská, Barbora; Ondroušková, Eva; Kubelková, Irena; Zapletalová, Danica; Tuček, Štěpán; Múdry, Peter; Krákorová, Dagmar Adámková; Knopfová, Lucia; Šmarda, Jan; Souček, Karel; Borsig, Lubor; Beneš, Petr
Transcription factor c-Myb: novel prognostic factor in osteosarcoma. Journal Article
In: Clinical & experimental metastasis, vol. 39, no. 2, pp. 375–390, 2022, ISSN: 1573-7276 0262-0898, (Place: Netherlands).
Abstract | Links | BibTeX | Tags: *Bone Neoplasms/pathology, *Osteosarcoma/pathology, Animals, c-Myb, Cell Line, Cell Movement/genetics, Cell Proliferation, Chemoresistance, Gene Expression Regulation, Humans, Metastasis, Mice, Neoplastic, Osteosarcoma, Prognosis, proliferation, Retrospective Studies, Tumor, Wnt Signaling Pathway
@article{rihova_transcription_2022,
title = {Transcription factor c-Myb: novel prognostic factor in osteosarcoma.},
author = {Kamila Říhová and Monika Dúcka and Iva Staniczková Zambo and Ladislava Vymětalová and Martin Šrámek and Filip Trčka and Jan Verner and Stanislav Drápela and Radek Fedr and Tereza Suchánková and Barbora Pavlatovská and Eva Ondroušková and Irena Kubelková and Danica Zapletalová and Štěpán Tuček and Peter Múdry and Dagmar Adámková Krákorová and Lucia Knopfová and Jan Šmarda and Karel Souček and Lubor Borsig and Petr Beneš},
doi = {10.1007/s10585-021-10145-4},
issn = {1573-7276 0262-0898},
year = {2022},
date = {2022-04-01},
journal = {Clinical & experimental metastasis},
volume = {39},
number = {2},
pages = {375–390},
abstract = {The transcription factor c-Myb is an oncoprotein promoting cell proliferation and survival when aberrantly activated/expressed, thus contributing to malignant transformation. Overexpression of c-Myb has been found in leukemias, breast, colon and adenoid cystic carcinoma. Recent studies revealed its expression also in osteosarcoma cell lines and suggested its functional importance during bone development. However, the relevance of c-Myb in control of osteosarcoma progression remains unknown. A retrospective clinical study was carried out to assess a relationship between c-Myb expression in archival osteosarcoma tissues and prognosis in a cohort of high-grade osteosarcoma patients. In addition, MYB was depleted in metastatic osteosarcoma cell lines SAOS-2 LM5 and 143B and their growth, chemosensitivity, migration and metastatic activity were determined. Immunohistochemical analysis revealed that high c-Myb expression was significantly associated with poor overall survival in the cohort and metastatic progression in young patients. Increased level of c-Myb was detected in metastatic osteosarcoma cell lines and its depletion suppressed their growth, colony-forming capacity, migration and chemoresistance in vitro in a cell line-dependent manner. MYB knock-out resulted in reduced metastatic activity of both SAOS-2 LM5 and 143B cell lines in immunodeficient mice. Transcriptomic analysis revealed the c-Myb-driven functional programs enriched for genes involved in the regulation of cell growth, stress response, cell adhesion and cell differentiation/morphogenesis. Wnt signaling pathway was identified as c-Myb target in osteosarcoma cells. Taken together, we identified c-Myb as a negative prognostic factor in osteosarcoma and showed its involvement in the regulation of osteosarcoma cell growth, chemosensitivity, migration and metastatic activity.},
note = {Place: Netherlands},
keywords = {*Bone Neoplasms/pathology, *Osteosarcoma/pathology, Animals, c-Myb, Cell Line, Cell Movement/genetics, Cell Proliferation, Chemoresistance, Gene Expression Regulation, Humans, Metastasis, Mice, Neoplastic, Osteosarcoma, Prognosis, proliferation, Retrospective Studies, Tumor, Wnt Signaling Pathway},
pubstate = {published},
tppubtype = {article}
}
Šimečková, Pavlína; Pěnčíková, Kateřina; Kováč, Ondrej; Slavík, Josef; Pařenicová, Martina; Vondráček, Jan; Machala, Miroslav
In: The Science of the total environment, vol. 815, pp. 151967, 2022, ISSN: 1879-1026 0048-9697, (Place: Netherlands).
Abstract | Links | BibTeX | Tags: *Polycyclic Aromatic Hydrocarbons/toxicity, Aryl Hydrocarbon/genetics/metabolism, Benzo(a)pyrene, Cellular stress response, Cytoplasmic and Nuclear/genetics, Energy Metabolism, Humans, Nuclear receptors, Polycyclic aromatic hydrocarbons, Receptors, Signal Transduction, Sphingolipids, Xenobiotics
@article{simeckova_vitro_2022,
title = {In vitro profiling of toxic effects of environmental polycyclic aromatic hydrocarbons on nuclear receptor signaling, disruption of endogenous metabolism and induction of cellular stress.},
author = {Pavlína Šimečková and Kateřina Pěnčíková and Ondrej Kováč and Josef Slavík and Martina Pařenicová and Jan Vondráček and Miroslav Machala},
doi = {10.1016/j.scitotenv.2021.151967},
issn = {1879-1026 0048-9697},
year = {2022},
date = {2022-04-01},
journal = {The Science of the total environment},
volume = {815},
pages = {151967},
abstract = {Polycyclic aromatic hydrocarbons (PAHs) may interact with multiple intracellular receptors and related signaling pathways. We comprehensively evaluated the toxicity profiles of six environmentally relevant PAHs differing in structure, genotoxicity and their ability to activate the aryl hydrocarbon receptor (AhR). We focused particularly on their impact on intracellular hormone-, xenobiotic- and lipid-sensing receptors, as well as on cellular stress markers, combining a battery of human reporter gene assays and qRT-PCR evaluation of endogenous gene expression in human hepatocyte-like HepaRG cells, with LC/MS-MS analysis of cellular sphingolipids. The effects of PAHs included: activation of estrogen receptor α (in case of fluoranthene (Fla), pyrene (Pyr), benz[a]anthracene (BaA), benzo[a]pyrene (BaP)), suppression of androgen receptor activity (Fla, BaA, BaP and benzo[k]fluoranthene (BkF)), enhancement of dexamethasone-induced glucocorticoid receptor activity (chrysene (Chry), BaA, and BaP), and potentiation of triiodothyronine-induced thyroid receptor α activity (all tested PAHs). PAHs also induced transcription of endogenous gene targets of constitutive androstane receptor (Fla, Pyr), or repression of target genes of pregnane X receptor and peroxisome proliferator-activated receptor α (in case of the AhR-activating PAHs - Chry, BaA, BaP, and BkF) in HepaRG cells. In the same cell model, the AhR agonists reduced the expression of glucose metabolism genes (PCK1, G6PC and PDK4), and they up-regulated levels of glucosylceramides, together with a concomitant induction of expression of UGCG, glucosylceramide synthesis enzyme. Finally, both BaP and BkF were found to induce expression of early stress and genotoxicity markers: ATF3, EGR1, GDF15, CDKN1A/p21, and GADD45A mRNAs, while BaP alone increased levels of IL-6 mRNA. Overall, whereas low-molecular-weight PAHs exerted significant effects on nuclear receptors (with CYP2B6 induction observed already at nanomolar concentrations), the AhR activation by 4-ring and 5-ring PAHs appeared to be a key mechanism underlying their impact on nuclear receptor signaling, endogenous metabolism and induction of early stress and genotoxicity markers.},
note = {Place: Netherlands},
keywords = {*Polycyclic Aromatic Hydrocarbons/toxicity, Aryl Hydrocarbon/genetics/metabolism, Benzo(a)pyrene, Cellular stress response, Cytoplasmic and Nuclear/genetics, Energy Metabolism, Humans, Nuclear receptors, Polycyclic aromatic hydrocarbons, Receptors, Signal Transduction, Sphingolipids, Xenobiotics},
pubstate = {published},
tppubtype = {article}
}
Vázquez-Gómez, Gerardo; Karasová, Martina; Tylichová, Zuzana; Kabátková, Markéta; Hampl, Aleš; Matthews, Jason; Neča, Jiří; Ciganek, Miroslav; Machala, Miroslav; Vondráček, Jan
Aryl Hydrocarbon Receptor (AhR) Limits the Inflammatory Responses in Human Lung Adenocarcinoma A549 Cells via Interference with NF-κB Signaling. Journal Article
In: Cells, vol. 11, no. 4, 2022, ISSN: 2073-4409, (Place: Switzerland).
Abstract | Links | BibTeX | Tags: *Environmental Pollutants/toxicity, *Inflammation/pathology, *NF-kappa B/metabolism, *Receptors, A549 Cells, AhR, alveolar epithelial type II cells, Aryl Hydrocarbon/metabolism, cytokines, Humans, Inflammation, NF-κB, prostaglandins
@article{vazquez-gomez_aryl_2022,
title = {Aryl Hydrocarbon Receptor (AhR) Limits the Inflammatory Responses in Human Lung Adenocarcinoma A549 Cells via Interference with NF-κB Signaling.},
author = {Gerardo Vázquez-Gómez and Martina Karasová and Zuzana Tylichová and Markéta Kabátková and Aleš Hampl and Jason Matthews and Jiří Neča and Miroslav Ciganek and Miroslav Machala and Jan Vondráček},
doi = {10.3390/cells11040707},
issn = {2073-4409},
year = {2022},
date = {2022-02-01},
journal = {Cells},
volume = {11},
number = {4},
abstract = {Apart from its role in the metabolism of carcinogens, the aryl hydrocarbon receptor (AhR) has been suggested to be involved in the control of inflammatory responses within the respiratory tract. However, the mechanisms responsible for this are only partially known. In this study, we used A549 cell line, as a human model of lung alveolar type II (ATII)-like cells, to study the functional role of the AhR in control of inflammatory responses. Using IL-1β as an inflammation inducer, we found that the induction of cyclooxygenase-2 and secretion of prostaglandins, as well as expression and release of pro-inflammatory cytokines, were significantly higher in the AhR-deficient A549 cells. This was linked with an increased nuclear factor-κB (NF-κB) activity, and significantly enhanced phosphorylation of its regulators, IKKα/β, and their target IκBα, in the AhR-deficient A549 cells. In line with this, when we mimicked the exposure to a complex mixture of airborne pollutants, using an organic extract of reference diesel exhaust particle mixture, an exacerbated inflammatory response was observed in the AhR-deficient cells, as compared with wild-type A549 cells. Together, the present results indicate that the AhR may act as a negative regulator of the inflammatory response in the A549 model, via a direct modulation of NF-κB signaling. Its role(s) in the control of inflammation within the lung alveoli exposed to airborne pollutants, especially those which simultaneously activate the AhR, thus deserve further attention.},
note = {Place: Switzerland},
keywords = {*Environmental Pollutants/toxicity, *Inflammation/pathology, *NF-kappa B/metabolism, *Receptors, A549 Cells, AhR, alveolar epithelial type II cells, Aryl Hydrocarbon/metabolism, cytokines, Humans, Inflammation, NF-κB, prostaglandins},
pubstate = {published},
tppubtype = {article}
}
Krkoška, Martin; Nekvindová, Jana; Nevědělová, Kateřina; Zubáňová, Veronika; Radová, Lenka; Vondráček, Jan; Herůdková, Jarmila; Slabý, Ondřej; Kiss, Igor; Bohovicová, Lucia; Fabian, Pavel; Tylichová, Zuzana; Kala, Zdeněk; Kysela, Petr; Ostřížková, Lenka; Palička, Vladimír; Vaculová, Alena Hyršlová
Role of miR-653 and miR-29c in downregulation of CYP1A2 expression in hepatocellular carcinoma. Journal Article
In: Pharmacological reports : PR, vol. 74, no. 1, pp. 148–158, 2022, ISSN: 2299-5684 1734-1140, (Place: Switzerland).
Abstract | Links | BibTeX | Tags: *Carcinoma, *Liver Neoplasms/genetics/metabolism, AhR, Biotransformation, Cell Line, CYP1A2, Cytochrome P-450 CYP1A2/*metabolism, Down-Regulation, Gene Expression Regulation, Hepatocellular carcinoma, Hepatocellular/genetics/metabolism, Hepatocytes/metabolism, Humans, MicroRNA, MicroRNAs/*metabolism, Neoplastic, Tumor, Xenobiotics/metabolism
@article{krkoska_role_2022,
title = {Role of miR-653 and miR-29c in downregulation of CYP1A2 expression in hepatocellular carcinoma.},
author = {Martin Krkoška and Jana Nekvindová and Kateřina Nevědělová and Veronika Zubáňová and Lenka Radová and Jan Vondráček and Jarmila Herůdková and Ondřej Slabý and Igor Kiss and Lucia Bohovicová and Pavel Fabian and Zuzana Tylichová and Zdeněk Kala and Petr Kysela and Lenka Ostřížková and Vladimír Palička and Alena Hyršlová Vaculová},
doi = {10.1007/s43440-021-00338-9},
issn = {2299-5684 1734-1140},
year = {2022},
date = {2022-02-01},
journal = {Pharmacological reports : PR},
volume = {74},
number = {1},
pages = {148–158},
abstract = {BACKGROUND: Hepatocellular carcinoma (HCC) is a major contributor to the worldwide cancer burden. Recent studies on HCC have demonstrated dramatic alterations in expression of several cytochrome P450 (CYP) family members that play a crucial role in biotransformation of many drugs and other xenobiotics; however, the mechanisms responsible for their deregulation remain unclear. METHODS: We investigated a potential involvement of miRNAs in downregulation of expression of CYPs observed in HCC tumors. We compared miRNA expression profiles (TaqMan Array Human MicroRNA v3.0 TLDA qPCR) between HCC human patient tumors with strong (CYP-) and weak/no (CYP+) downregulation of drug-metabolizing CYPs. The role of significantly deregulated miRNAs in modulation of expression of the CYPs and associated xenobiotic receptors was then investigated in human liver HepaRG cells transfected with relevant miRNA mimics or inhibitors. RESULTS: We identified five differentially expressed miRNAs in CYP- versus CYP+ tumors, namely miR-29c, miR-125b1, miR-505, miR-653 and miR-675. The two most-upregulated miRNAs found in CYP- tumor samples, miR-29c and miR-653, were found to act as efficient suppressors of CYP1A2 or AHR expression. CONCLUSIONS: Our results revealed a novel role of miR-653 and miR-29c in regulation of expresion of CYPs involved in crucial biotransformation processes in liver, which are often deregulated during liver cancer progression.},
note = {Place: Switzerland},
keywords = {*Carcinoma, *Liver Neoplasms/genetics/metabolism, AhR, Biotransformation, Cell Line, CYP1A2, Cytochrome P-450 CYP1A2/*metabolism, Down-Regulation, Gene Expression Regulation, Hepatocellular carcinoma, Hepatocellular/genetics/metabolism, Hepatocytes/metabolism, Humans, MicroRNA, MicroRNAs/*metabolism, Neoplastic, Tumor, Xenobiotics/metabolism},
pubstate = {published},
tppubtype = {article}
}
Drápela, Stanislav; Fedr, Radek; Vacek, Ondřej; Remšík, Ján; Souček, Karel
High-Throughput, Parallel Flow Cytometry Screening of Hundreds of Cell Surface Antigens Using Fluorescent Barcoding. Journal Article
In: Methods in molecular biology (Clifton, N.J.), vol. 2543, pp. 99–111, 2022, ISSN: 1940-6029 1064-3745, (Place: United States).
Abstract | Links | BibTeX | Tags: *Antigens, *Research, Biomarkers/analysis, Cell surface phenotyping, Flow Cytometry, Fluorescent cell barcoding, Fluorescent Dyes, High-throughput screening, Multicolor flow cytometry, Surface
@article{drapela_high-throughput_2022,
title = {High-Throughput, Parallel Flow Cytometry Screening of Hundreds of Cell Surface Antigens Using Fluorescent Barcoding.},
author = {Stanislav Drápela and Radek Fedr and Ondřej Vacek and Ján Remšík and Karel Souček},
doi = {10.1007/978-1-0716-2553-8_9},
issn = {1940-6029 1064-3745},
year = {2022},
date = {2022-01-01},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {2543},
pages = {99–111},
abstract = {Multicolor flow cytometry allows for analysis of tens of cellular parameters in millions of cells at a single-cell resolution within minutes. The lack of technologies that would facilitate feasible and relatively cheap profiling of such a number of cells with an antibody-based approach led us to the development of a high-throughput cytometry-based platform for surface profiling. We coupled the fluorescent cell barcoding with preexisting, commercially available screening tools to analyze cell surface fingerprint at a large scale. This powerful approach will help to identify novel biomarkers and druggable targets and facilitate the discovery of new concepts in immunology, oncology, and developmental biology.},
note = {Place: United States},
keywords = {*Antigens, *Research, Biomarkers/analysis, Cell surface phenotyping, Flow Cytometry, Fluorescent cell barcoding, Fluorescent Dyes, High-throughput screening, Multicolor flow cytometry, Surface},
pubstate = {published},
tppubtype = {article}
}
2021
Slabáková, Eva; Kahounová, Zuzana; Procházková, Jiřina; Souček, Karel
Regulation of Neuroendocrine-like Differentiation in Prostate Cancer by Non-Coding RNAs. Journal Article
In: Non-coding RNA, vol. 7, no. 4, 2021, ISSN: 2311-553X, (Place: Switzerland).
Abstract | Links | BibTeX | Tags: exosomes, extracellular vesicles, liquid biomarkers, lncRNA, MicroRNA, neuroendocrine differentiation/transdifferentiation, patients’ dataset, Prostate cancer
@article{slabakova_regulation_2021,
title = {Regulation of Neuroendocrine-like Differentiation in Prostate Cancer by Non-Coding RNAs.},
author = {Eva Slabáková and Zuzana Kahounová and Jiřina Procházková and Karel Souček},
doi = {10.3390/ncrna7040075},
issn = {2311-553X},
year = {2021},
date = {2021-12-01},
journal = {Non-coding RNA},
volume = {7},
number = {4},
abstract = {Neuroendocrine prostate cancer (NEPC) represents a variant of prostate cancer that occurs in response to treatment resistance or, to a much lesser extent, de novo. Unravelling the molecular mechanisms behind transdifferentiation of cancer cells to neuroendocrine-like cancer cells is essential for development of new treatment opportunities. This review focuses on summarizing the role of small molecules, predominantly microRNAs, in this phenomenon. A published literature search was performed to identify microRNAs, which are reported and experimentally validated to modulate neuroendocrine markers and/or regulators and to affect the complex neuroendocrine phenotype. Next, available patients' expression datasets were surveyed to identify deregulated microRNAs, and their effect on NEPC and prostate cancer progression is summarized. Finally, possibilities of miRNA detection and quantification in body fluids of prostate cancer patients and their possible use as liquid biopsy in prostate cancer monitoring are discussed. All the addressed clinical and experimental contexts point to an association of NEPC with upregulation of miR-375 and downregulation of miR-34a and miR-19b-3p. Together, this review provides an overview of different roles of non-coding RNAs in the emergence of neuroendocrine prostate cancer.},
note = {Place: Switzerland},
keywords = {exosomes, extracellular vesicles, liquid biomarkers, lncRNA, MicroRNA, neuroendocrine differentiation/transdifferentiation, patients’ dataset, Prostate cancer},
pubstate = {published},
tppubtype = {article}
}
Radaszkiewicz, Tomasz; Nosková, Michaela; Gömöryová, Kristína; Blanářová, Olga Vondálová; Radaszkiewicz, Katarzyna Anna; Picková, Markéta; Víchová, Ráchel; Gybeľ, Tomáš; Kaiser, Karol; Demková, Lucia; Kučerová, Lucia; Bárta, Tomáš; Potěšil, David; Zdráhal, Zbyněk; Souček, Karel; Bryja, Vítězslav
RNF43 inhibits WNT5A-driven signaling and suppresses melanoma invasion and resistance to the targeted therapy. Journal Article
In: eLife, vol. 10, 2021, ISSN: 2050-084X, (Place: England).
Abstract | Links | BibTeX | Tags: *Melanoma/genetics/pathology/prevention & control, *Signal Transduction, Animals, BRAF V600E, cancer biology, cell biology, human, Inbred NOD, Male, Melanoma, Mice, mouse, Neoplasm Invasiveness/genetics, RNF43, ROR1, Ubiquitin-Protein Ligases/*genetics/metabolism, VANGL1, Wnt-5a Protein/*genetics/metabolism, WNT5A
@article{radaszkiewicz_rnf43_2021,
title = {RNF43 inhibits WNT5A-driven signaling and suppresses melanoma invasion and resistance to the targeted therapy.},
author = {Tomasz Radaszkiewicz and Michaela Nosková and Kristína Gömöryová and Olga Vondálová Blanářová and Katarzyna Anna Radaszkiewicz and Markéta Picková and Ráchel Víchová and Tomáš Gybeľ and Karol Kaiser and Lucia Demková and Lucia Kučerová and Tomáš Bárta and David Potěšil and Zbyněk Zdráhal and Karel Souček and Vítězslav Bryja},
doi = {10.7554/eLife.65759},
issn = {2050-084X},
year = {2021},
date = {2021-10-01},
journal = {eLife},
volume = {10},
abstract = {RNF43 is an E3 ubiquitin ligase and known negative regulator of WNT/β-catenin signaling. We demonstrate that RNF43 is also a regulator of noncanonical WNT5A-induced signaling in human cells. Analysis of the RNF43 interactome using BioID and immunoprecipitation showed that RNF43 can interact with the core receptor complex components dedicated to the noncanonical Wnt pathway such as ROR1, ROR2, VANGL1, and VANGL2. RNF43 triggers VANGL2 ubiquitination and proteasomal degradation and clathrin-dependent internalization of ROR1 receptor and inhibits ROR2 activation. These activities of RNF43 are physiologically relevant and block pro-metastatic WNT5A signaling in melanoma. RNF43 inhibits responses to WNT5A, which results in the suppression of invasive properties of melanoma cells. Furthermore, RNF43 prevented WNT5A-assisted development of resistance to BRAF V600E and MEK inhibitors. Next, RNF43 acted as melanoma suppressor and improved response to targeted therapies in vivo. In line with these findings, RNF43 expression decreases during melanoma progression and RNF43-low patients have a worse prognosis. We conclude that RNF43 is a newly discovered negative regulator of WNT5A-mediated biological responses that desensitizes cells to WNT5A.},
note = {Place: England},
keywords = {*Melanoma/genetics/pathology/prevention & control, *Signal Transduction, Animals, BRAF V600E, cancer biology, cell biology, human, Inbred NOD, Male, Melanoma, Mice, mouse, Neoplasm Invasiveness/genetics, RNF43, ROR1, Ubiquitin-Protein Ligases/*genetics/metabolism, VANGL1, Wnt-5a Protein/*genetics/metabolism, WNT5A},
pubstate = {published},
tppubtype = {article}
}
Krkoška, Martin; Svobodová, Jana; Kabátková, Markéta; Zapletal, Ondřej; Vaculová, Alena Hyršlová; Nekvindová, Jana; Vondráček, Jan
In: Toxicology, vol. 461, pp. 152897, 2021, ISSN: 1879-3185 0300-483X, (Place: Ireland).
Abstract | Links | BibTeX | Tags: AhR, Cancer cells, Cell Line, Cell Proliferation, Cell Proliferation/*physiology, Cell Survival/physiology, Colonic Neoplasms/genetics/*pathology, CYP1 enzymes, Cytochrome P-450 CYP1A1/biosynthesis/*genetics, E1A-Associated p300 Protein/metabolism, Enzyme Induction/physiology, Gene Expression Regulation, HCT116 Cells, Hippo Signaling Pathway/physiology, Humans, Liver/*pathology, Neoplastic, p300, Signal Transduction/physiology, Tumor, Wnt Signaling Pathway/physiology, β-Catenin signaling
@article{krkoska_deregulation_2021,
title = {Deregulation of signaling pathways controlling cell survival and proliferation in cancer cells alters induction of cytochrome P450 family 1 enzymes.},
author = {Martin Krkoška and Jana Svobodová and Markéta Kabátková and Ondřej Zapletal and Alena Hyršlová Vaculová and Jana Nekvindová and Jan Vondráček},
doi = {10.1016/j.tox.2021.152897},
issn = {1879-3185 0300-483X},
year = {2021},
date = {2021-09-01},
journal = {Toxicology},
volume = {461},
pages = {152897},
abstract = {Cytochrome P450 family 1 (CYP1) enzymes contribute both to metabolism of xenobiotics and to the control of endogenous levels of ligands of the aryl hydrocarbon receptor (AhR). Their activities, similar to other CYPs, can be altered in tumor tissues. Here, we examined a possible role of proliferative/survival pathways signaling, which is often deregulated in tumor cells, and possible links with p300 histone acetyltransferase (a transcriptional co-activator) in the control of CYP1 expression, focusing particularly on CYP1A1. Using cell models derived from human liver, we observed that the induction of CYP1A1 expression, as well as other CYP1 enzymes, was reduced in exponentially growing cells, as compared with their non-dividing counterparts. The siRNA-mediated inhibition of proliferation/pro-survival signaling pathway effectors (such as β-catenin and/or Hippo pathway effectors YAP/TAZ) increased the AhR ligand-induced CYP1A1 mRNA levels in liver HepaRG cells, and/or in colon carcinoma HCT-116 cells. The activation of proliferative Wnt/β-catenin signaling in HCT-116 cells reduced both the induction of CYP1 enzymes and the binding of p300 to the promoter of CYP1A1 or CYP1B1 genes. These results seem to indicate that aberrant proliferative signaling in tumor cells could suppress induction of CYP1A1 (or other CYP1 enzymes) via competition for p300 binding. This mechanism could be involved in modulation of the metabolism of both endogenous and exogenous substrates of CYP1A1 (and other CYP1 enzymes), with possible further consequences for alterations of the AhR signaling in tumor cells, or additional functional roles of CYP1 enzymes.},
note = {Place: Ireland},
keywords = {AhR, Cancer cells, Cell Line, Cell Proliferation, Cell Proliferation/*physiology, Cell Survival/physiology, Colonic Neoplasms/genetics/*pathology, CYP1 enzymes, Cytochrome P-450 CYP1A1/biosynthesis/*genetics, E1A-Associated p300 Protein/metabolism, Enzyme Induction/physiology, Gene Expression Regulation, HCT116 Cells, Hippo Signaling Pathway/physiology, Humans, Liver/*pathology, Neoplastic, p300, Signal Transduction/physiology, Tumor, Wnt Signaling Pathway/physiology, β-Catenin signaling},
pubstate = {published},
tppubtype = {article}
}
Machala, Miroslav; Slavík, Josef; Kováč, Ondrej; Procházková, Jiřina; Pěnčíková, Kateřina; Pařenicová, Martina; Straková, Nicol; Kotouček, Jan; Kulich, Pavel; Mollerup, Steen; Vondráček, Jan; Hýžďalová, Martina
In: International journal of molecular sciences, vol. 22, no. 17, 2021, ISSN: 1422-0067, (Place: Switzerland).
Abstract | Links | BibTeX | Tags: *Cell Transformation, Benzo(a)pyrene/toxicity, Bronchi/cytology, Carcinogens/toxicity, Cell Line, eicosanoids, exosomes, Exosomes/*metabolism, glycosphingolipid, Humans, in vitro cell transformation, Neoplastic, Respiratory Mucosa/drug effects/*metabolism, sphingolipid, Sphingolipids/*metabolism
@article{machala_changes_2021,
title = {Changes in Sphingolipid Profile of Benzo[a]pyrene-Transformed Human Bronchial Epithelial Cells Are Reflected in the Altered Composition of Sphingolipids in Their Exosomes.},
author = {Miroslav Machala and Josef Slavík and Ondrej Kováč and Jiřina Procházková and Kateřina Pěnčíková and Martina Pařenicová and Nicol Straková and Jan Kotouček and Pavel Kulich and Steen Mollerup and Jan Vondráček and Martina Hýžďalová},
doi = {10.3390/ijms22179195},
issn = {1422-0067},
year = {2021},
date = {2021-08-01},
journal = {International journal of molecular sciences},
volume = {22},
number = {17},
abstract = {Sphingolipids (SLs), glycosphingolipids (GSLs), and eicosanoids are bioactive lipids, which play important roles in the etiology of various diseases, including cancer. However, their content and roles in cancer cells, and in particular in the exosomes derived from tumor cells, remain insufficiently characterized. In this study, we evaluated alterations of SL and GSL levels in transformed cells and their exosomes, using comparative HPLC-MS/MS analysis of parental human bronchial epithelial cells HBEC-12KT and their derivative, benzo[a]pyrene-transformed HBEC-12KT-B1 cells with the acquired mesenchymal phenotype. We examined in parallel SL/GSL contents in the exosomes released from both cell lines. We found significant alterations of the SL/GSL profile in the transformed cell line, which corresponded well with alterations of the SL/GSL profile in exosomes derived from these cells. This suggested that a majority of SLs and GSLs were transported by exosomes in the same relative pattern as in the cells of origin. The only exceptions included decreased contents of sphingosin, sphingosin-1-phosphate, and lactosylceramide in exosomes derived from the transformed cells, as compared with the exosomes derived from the parental cell line. Importantly, we found increased levels of ceramide phosphate, globoside Gb3, and ganglioside GD3 in the exosomes derived from the transformed cells. These positive modulators of epithelial-mesenchymal transition and other pro-carcinogenic processes might thus also contribute to cancer progression in recipient cells. In addition, the transformed HBEC-12KT-B1 cells also produced increased amounts of eicosanoids, in particular prostaglandin E2. Taken together, the exosomes derived from the transformed cells with specifically upregulated SL and GSL species, and increased levels of eicosanoids, might contribute to changes within the cancer microenvironment and in recipient cells, which could in turn participate in cancer development. Future studies should address specific roles of individual SL and GSL species identified in the present study.},
note = {Place: Switzerland},
keywords = {*Cell Transformation, Benzo(a)pyrene/toxicity, Bronchi/cytology, Carcinogens/toxicity, Cell Line, eicosanoids, exosomes, Exosomes/*metabolism, glycosphingolipid, Humans, in vitro cell transformation, Neoplastic, Respiratory Mucosa/drug effects/*metabolism, sphingolipid, Sphingolipids/*metabolism},
pubstate = {published},
tppubtype = {article}
}
Hofmanová, Jiřina; Slavík, Josef; Ciganek, Miroslav; Ovesná, Petra; Tylichová, Zuzana; Karasová, Martina; Zapletal, Ondřej; Straková, Nicol; Procházková, Jiřina; Bouchal, Jan; Kolář, Zdeněk; Ehrmann, Jiří; Levková, Monika; Hušková, Zlatka; Skalický, Pavel; Kozubík, Alois; Machala, Miroslav; Vondráček, Jan
Complex Alterations of Fatty Acid Metabolism and Phospholipidome Uncovered in Isolated Colon Cancer Epithelial Cells. Journal Article
In: International journal of molecular sciences, vol. 22, no. 13, 2021, ISSN: 1422-0067, (Place: Switzerland).
Abstract | Links | BibTeX | Tags: *Gene Expression Regulation, *Lipid Metabolism, Adenocarcinoma/enzymology/genetics/*metabolism, Aged, Colonic Neoplasms/enzymology/genetics/*metabolism, colorectal carcinoma, desaturation, EpCAM, Epithelial Cells, Epithelial Cells/enzymology/metabolism, Fatty Acid Desaturases/genetics/metabolism, Fatty Acid Elongases/genetics/metabolism, Fatty Acid Synthases/genetics/metabolism, fatty acid synthesis, Fatty Acids/*metabolism, Female, Humans, lipidomics, Lipogenesis, lysophospholipids, Male, Neoplastic, Phospholipids, Phospholipids/*metabolism, Stearoyl-CoA Desaturase/genetics/metabolism
@article{hofmanova_complex_2021,
title = {Complex Alterations of Fatty Acid Metabolism and Phospholipidome Uncovered in Isolated Colon Cancer Epithelial Cells.},
author = {Jiřina Hofmanová and Josef Slavík and Miroslav Ciganek and Petra Ovesná and Zuzana Tylichová and Martina Karasová and Ondřej Zapletal and Nicol Straková and Jiřina Procházková and Jan Bouchal and Zdeněk Kolář and Jiří Ehrmann and Monika Levková and Zlatka Hušková and Pavel Skalický and Alois Kozubík and Miroslav Machala and Jan Vondráček},
doi = {10.3390/ijms22136650},
issn = {1422-0067},
year = {2021},
date = {2021-06-01},
journal = {International journal of molecular sciences},
volume = {22},
number = {13},
abstract = {The development of colon cancer, one of the most common malignancies, is accompanied with numerous lipid alterations. However, analyses of whole tumor samples may not always provide an accurate description of specific changes occurring directly in tumor epithelial cells. Here, we analyzed in detail the phospholipid (PL), lysophospholipid (lysoPL), and fatty acid (FA) profiles of purified EpCAM(+) cells, isolated from tumor and adjacent non-tumor tissues of colon cancer patients. We found that a number of FAs increased significantly in isolated tumor cells, which also included a number of long polyunsaturated FAs. Higher levels of FAs were associated with increased expression of FA synthesis genes, as well as with altered expression of enzymes involved in FA elongation and desaturation, including particularly fatty acid synthase, stearoyl-CoA desaturase, fatty acid desaturase 2 and ELOVL5 fatty acid elongase 5 We identified significant changes in ratios of specific lysoPLs and corresponding PLs. A number of lysophosphatidylcholine and lysophosphatidylethanolamine species, containing long-chain and very-long chain FAs, often with high numbers of double bonds, were significantly upregulated in tumor cells. Increased de novo synthesis of very long-chain FAs, or, altered uptake or incorporation of these FAs into specific lysoPLs in tumor cells, may thus contribute to reprogramming of cellular phospholipidome and membrane alterations observed in colon cancer.},
note = {Place: Switzerland},
keywords = {*Gene Expression Regulation, *Lipid Metabolism, Adenocarcinoma/enzymology/genetics/*metabolism, Aged, Colonic Neoplasms/enzymology/genetics/*metabolism, colorectal carcinoma, desaturation, EpCAM, Epithelial Cells, Epithelial Cells/enzymology/metabolism, Fatty Acid Desaturases/genetics/metabolism, Fatty Acid Elongases/genetics/metabolism, Fatty Acid Synthases/genetics/metabolism, fatty acid synthesis, Fatty Acids/*metabolism, Female, Humans, lipidomics, Lipogenesis, lysophospholipids, Male, Neoplastic, Phospholipids, Phospholipids/*metabolism, Stearoyl-CoA Desaturase/genetics/metabolism},
pubstate = {published},
tppubtype = {article}
}
Kvokačková, Barbora; Remšík, Ján; Jolly, Mohit Kumar; Souček, Karel
Phenotypic Heterogeneity of Triple-Negative Breast Cancer Mediated by Epithelial-Mesenchymal Plasticity. Journal Article
In: Cancers, vol. 13, no. 9, 2021, ISSN: 2072-6694, (Place: Switzerland).
Abstract | Links | BibTeX | Tags: epithelial–mesenchymal transition, mesenchymal–epithelial transition, Metastasis, Plasticity, triple-negative breast cancer
@article{kvokackova_phenotypic_2021,
title = {Phenotypic Heterogeneity of Triple-Negative Breast Cancer Mediated by Epithelial-Mesenchymal Plasticity.},
author = {Barbora Kvokačková and Ján Remšík and Mohit Kumar Jolly and Karel Souček},
doi = {10.3390/cancers13092188},
issn = {2072-6694},
year = {2021},
date = {2021-05-01},
journal = {Cancers},
volume = {13},
number = {9},
abstract = {Triple-negative breast cancer (TNBC) is a subtype of breast carcinoma known for its unusually aggressive behavior and poor clinical outcome. Besides the lack of molecular targets for therapy and profound intratumoral heterogeneity, the relatively quick overt metastatic spread remains a major obstacle in effective clinical management. The metastatic colonization of distant sites by primary tumor cells is affected by the microenvironment, epigenetic state of particular subclones, and numerous other factors. One of the most prominent processes contributing to the intratumoral heterogeneity is an epithelial-mesenchymal transition (EMT), an evolutionarily conserved developmental program frequently hijacked by tumor cells, strengthening their motile and invasive features. In response to various intrinsic and extrinsic stimuli, malignant cells can revert the EMT state through the mesenchymal-epithelial transition (MET), a process that is believed to be critical for the establishment of macrometastasis at secondary sites. Notably, cancer cells rarely undergo complete EMT and rather exist in a continuum of E/M intermediate states, preserving high levels of plasticity, as demonstrated in primary tumors and, ultimately, in circulating tumor cells, representing a simplified element of the metastatic cascade. In this review, we focus on cellular drivers underlying EMT/MET phenotypic plasticity and its detrimental consequences in the context of TNBC cancer.},
note = {Place: Switzerland},
keywords = {epithelial–mesenchymal transition, mesenchymal–epithelial transition, Metastasis, Plasticity, triple-negative breast cancer},
pubstate = {published},
tppubtype = {article}
}
Němec, Václav; Maier, Lukáš; Berger, Benedict-Tilman; Chaikuad, Apirat; Drápela, Stanislav; Souček, Karel; Knapp, Stefan; Paruch, Kamil
Highly selective inhibitors of protein kinases CLK and HIPK with the furo[3,2-b]pyridine core. Journal Article
In: European journal of medicinal chemistry, vol. 215, pp. 113299, 2021, ISSN: 1768-3254 0223-5234, (Place: France).
Abstract | Links | BibTeX | Tags: 2-b]pyridine, Animals, Carrier Proteins/*antagonists & inhibitors/metabolism, CLK, Crystallography, Furans/chemical synthesis/metabolism/*pharmacology, Furo[3, HIPK, Humans, Inhibitor, Kinase, MCF-7 Cells, Mice, Molecular Structure, MU1210, MU135, MU1787, Protein Binding, Protein Kinase Inhibitors/chemical synthesis/metabolism/*pharmacology, Protein Serine-Threonine Kinases/*antagonists & inhibitors/metabolism, Pyridines/chemical synthesis/metabolism/*pharmacology, Structure-Activity Relationship, X-Ray
@article{nemec_highly_2021,
title = {Highly selective inhibitors of protein kinases CLK and HIPK with the furo[3,2-b]pyridine core.},
author = {Václav Němec and Lukáš Maier and Benedict-Tilman Berger and Apirat Chaikuad and Stanislav Drápela and Karel Souček and Stefan Knapp and Kamil Paruch},
doi = {10.1016/j.ejmech.2021.113299},
issn = {1768-3254 0223-5234},
year = {2021},
date = {2021-04-01},
journal = {European journal of medicinal chemistry},
volume = {215},
pages = {113299},
abstract = {The furo [3,2-b]pyridine motif represents a relatively underexplored central pharmacophore in the area of kinase inhibitors. Herein, we report flexible synthesis of 3,5-disubstituted furo [3,2-b]pyridines that relies on chemoselective couplings of newly prepared 5-chloro-3-iodofuro [3,2-b]pyridine. This methodology allowed efficient second-generation synthesis of the state-of-the-art chemical biology probe for CLK1/2/4 MU1210, and identification of the highly selective inhibitors of HIPKs MU135 and MU1787 which are presented and characterized in this study, including the X-ray crystal structure of MU135 in HIPK2. chemical biology probe.},
note = {Place: France},
keywords = {2-b]pyridine, Animals, Carrier Proteins/*antagonists & inhibitors/metabolism, CLK, Crystallography, Furans/chemical synthesis/metabolism/*pharmacology, Furo[3, HIPK, Humans, Inhibitor, Kinase, MCF-7 Cells, Mice, Molecular Structure, MU1210, MU135, MU1787, Protein Binding, Protein Kinase Inhibitors/chemical synthesis/metabolism/*pharmacology, Protein Serine-Threonine Kinases/*antagonists & inhibitors/metabolism, Pyridines/chemical synthesis/metabolism/*pharmacology, Structure-Activity Relationship, X-Ray},
pubstate = {published},
tppubtype = {article}
}
Mickova, Alena; Kharaishvili, Gvantsa; Kurfurstova, Daniela; Gachechiladze, Mariam; Kral, Milan; Vacek, Ondrej; Pokryvkova, Barbora; Mistrik, Martin; Soucek, Karel; Bouchal, Jan
Skp2 and Slug Are Coexpressed in Aggressive Prostate Cancer and Inhibited by Neddylation Blockade. Journal Article
In: International journal of molecular sciences, vol. 22, no. 6, 2021, ISSN: 1422-0067, (Place: Switzerland).
Abstract | Links | BibTeX | Tags: *Protein Processing, Androgen/genetics/metabolism, Antigens, Antineoplastic Agents/pharmacology, Cadherins/genetics/metabolism, CD/genetics/metabolism, Cell Line, Cell Survival/drug effects, Cyclin-Dependent Kinase Inhibitor p27/genetics/metabolism, Cyclopentanes/pharmacology, Docetaxel/pharmacology, Epithelial-Mesenchymal Transition/genetics, Gene Expression Regulation, Humans, Immunohistochemistry, Lymphatic Metastasis, Male, multiplex, NEDD8 Protein/*genetics/metabolism, neddylation, Neoplasm Grading, Neoplastic, PC-3 Cells, Post-Translational, Prostate cancer, Prostate/metabolism/pathology, Prostatic Neoplasms/*genetics/metabolism/pathology, Pyrimidines/pharmacology, Receptors, RNA, S-Phase Kinase-Associated Proteins/antagonists & inhibitors/*genetics/metabolism, Skp2 (S-phase kinase-associated protein 2), Slug, Small Interfering/genetics/metabolism, Snail Family Transcription Factors/*genetics/metabolism, Tumor
@article{mickova_skp2_2021,
title = {Skp2 and Slug Are Coexpressed in Aggressive Prostate Cancer and Inhibited by Neddylation Blockade.},
author = {Alena Mickova and Gvantsa Kharaishvili and Daniela Kurfurstova and Mariam Gachechiladze and Milan Kral and Ondrej Vacek and Barbora Pokryvkova and Martin Mistrik and Karel Soucek and Jan Bouchal},
doi = {10.3390/ijms22062844},
issn = {1422-0067},
year = {2021},
date = {2021-03-01},
journal = {International journal of molecular sciences},
volume = {22},
number = {6},
abstract = {Prostate cancer (PCa) is the second leading cause of cancer-related deaths in men in Western countries, and there is still an urgent need for a better understanding of PCa progression to inspire new treatment strategies. Skp2 is a substrate-recruiting component of the E3 ubiquitin ligase complex, whose activity is regulated through neddylation. Slug is a transcriptional repressor involved in the epithelial-to-mesenchymal transition, which may contribute to therapy resistance. Although Skp2 has previously been associated with a mesenchymal phenotype and prostate cancer progression, the relationship with Slug deserves further elucidation. We have previously shown that a high Gleason score (≥8) is associated with higher Skp2 and lower E-cadherin expression. In this study, significantly increased expression of Skp2, AR, and Slug, along with E-cadherin downregulation, was observed in primary prostate cancer in patients who already had lymph node metastases. Skp2 was slightly correlated with Slug and AR in the whole cohort (Rs 0.32 and 0.37, respectively), which was enhanced for both proteins in patients with high Gleason scores (Rs 0.56 and 0.53, respectively) and, in the case of Slug, also in patients with metastasis to lymph nodes (Rs 0.56). Coexpression of Skp2 and Slug was confirmed in prostate cancer tissues by multiplex immunohistochemistry and confocal microscopy. The same relationship between these two proteins was observed in three sets of prostate epithelial cell lines (PC3, DU145, and E2) and their mesenchymal counterparts. Chemical inhibition of Skp2, but not RNA interference, modestly decreased Slug protein in PC3 and its docetaxel-resistant subline PC3 DR12. Importantly, chemical inhibition of Skp2 by MLN4924 upregulated p27 and decreased Slug expression in PC3, PC3 DR12, and LAPC4 cells. Novel treatment strategies targeting Skp2 and Slug by the neddylation blockade may be promising in advanced prostate cancer, as recently documented for other aggressive solid tumors.},
note = {Place: Switzerland},
keywords = {*Protein Processing, Androgen/genetics/metabolism, Antigens, Antineoplastic Agents/pharmacology, Cadherins/genetics/metabolism, CD/genetics/metabolism, Cell Line, Cell Survival/drug effects, Cyclin-Dependent Kinase Inhibitor p27/genetics/metabolism, Cyclopentanes/pharmacology, Docetaxel/pharmacology, Epithelial-Mesenchymal Transition/genetics, Gene Expression Regulation, Humans, Immunohistochemistry, Lymphatic Metastasis, Male, multiplex, NEDD8 Protein/*genetics/metabolism, neddylation, Neoplasm Grading, Neoplastic, PC-3 Cells, Post-Translational, Prostate cancer, Prostate/metabolism/pathology, Prostatic Neoplasms/*genetics/metabolism/pathology, Pyrimidines/pharmacology, Receptors, RNA, S-Phase Kinase-Associated Proteins/antagonists & inhibitors/*genetics/metabolism, Skp2 (S-phase kinase-associated protein 2), Slug, Small Interfering/genetics/metabolism, Snail Family Transcription Factors/*genetics/metabolism, Tumor},
pubstate = {published},
tppubtype = {article}
}
Hýžďalová, Martina; Procházková, Jiřina; Strapáčová, Simona; Svržková, Lucie; Vacek, Ondřej; Fedr, Radek; Andrysík, Zdeněk; Hrubá, Eva; Líbalová, Helena; Kléma, Jiří; Topinka, Jan; Mašek, Josef; Souček, Karel; Vondráček, Jan; Machala, Miroslav
In: Chemosphere, vol. 263, pp. 128126, 2021, ISSN: 1879-1298 0045-6535, (Place: England).
Abstract | Links | BibTeX | Tags: *Carcinoma, *Lung Neoplasms/genetics, Aryl Hydrocarbon/genetics, BaP, Benzo(a)pyrene/toxicity, Cell Proliferation, EMT, Epithelial Cells, Humans, Lung, Lung carcinoma, Phenotype, Receptors, TCDD, Tumor progression
@article{hyzdalova_prolonged_2021,
title = {A prolonged exposure of human lung carcinoma epithelial cells to benzo[a]pyrene induces p21-dependent epithelial-to-mesenchymal transition (EMT)-like phenotype.},
author = {Martina Hýžďalová and Jiřina Procházková and Simona Strapáčová and Lucie Svržková and Ondřej Vacek and Radek Fedr and Zdeněk Andrysík and Eva Hrubá and Helena Líbalová and Jiří Kléma and Jan Topinka and Josef Mašek and Karel Souček and Jan Vondráček and Miroslav Machala},
doi = {10.1016/j.chemosphere.2020.128126},
issn = {1879-1298 0045-6535},
year = {2021},
date = {2021-01-01},
journal = {Chemosphere},
volume = {263},
pages = {128126},
abstract = {Deciphering the role of the aryl hydrocarbon receptor (AhR) in lung cancer cells may help us to better understand the role of toxic AhR ligands in lung carcinogenesis, including cancer progression. We employed human lung carcinoma A549 cells to investigate their fate after continuous two-week exposure to model AhR agonists, genotoxic benzo[a]pyrene (BaP; 1 μM) and non-genotoxic 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; 10 nM). While TCDD increased proliferative rate of A549 cells, exposure to BaP decreased cell proliferation and induced epithelial-to-mesenchymal transition (EMT)-like phenotype, which was associated with enhanced cell migration, invasion, and altered cell morphology. Although TCDD also suppressed expression of E-cadherin and activated some genes linked to EMT, it did not induce the EMT-like phenotype. The results of transcriptomic analysis, and the opposite effects of BaP and TCDD on cell proliferation, indicated that a delay in cell cycle progression, together with a slight increase of senescence (when coupled with AhR activation), favors the induction of EMT-like phenotype. The shift towards EMT-like phenotype observed after simultaneous treatment with TCDD and mitomycin C (an inhibitor of cell proliferation) confirmed the hypothesis. Since BaP decreased cell proliferative rate via induction of p21 expression, we generated the A549 cell model with reduced p21 expression and exposed it to BaP for two weeks. The p21 knockdown suppressed the BaP-mediated EMT-like phenotype in A549 cells, thus confirming that a delayed cell cycle progression, together with p21-dependent induction of senescence-related chemokine CCL2, may contribute to induction of EMT-like cell phenotype in lung cells exposed to genotoxic AhR ligands.},
note = {Place: England},
keywords = {*Carcinoma, *Lung Neoplasms/genetics, Aryl Hydrocarbon/genetics, BaP, Benzo(a)pyrene/toxicity, Cell Proliferation, EMT, Epithelial Cells, Humans, Lung, Lung carcinoma, Phenotype, Receptors, TCDD, Tumor progression},
pubstate = {published},
tppubtype = {article}
}
Vondráček, Jan; Machala, Miroslav
The Role of Metabolism in Toxicity of Polycyclic Aromatic Hydrocarbons and their Non-genotoxic Modes of Action. Journal Article
In: Current drug metabolism, vol. 22, no. 8, pp. 584–595, 2021, ISSN: 1875-5453 1389-2002, (Place: Netherlands).
Abstract | Links | BibTeX | Tags: Activation, AhR, Animals, Benzo[a]pyrene, Cell Proliferation, Cell Survival, cell-to-cell communication, DNA Damage, Environmental Pollutants/*pharmacokinetics/*toxicity, Humans, Metabolic, Mutagens/*pharmacokinetics/*toxicity, oxidative stress, PAH metabolism., Polycyclic Aromatic Hydrocarbons/*pharmacokinetics/*toxicity
@article{vondracek_role_2021,
title = {The Role of Metabolism in Toxicity of Polycyclic Aromatic Hydrocarbons and their Non-genotoxic Modes of Action.},
author = {Jan Vondráček and Miroslav Machala},
doi = {10.2174/1389200221999201125205725},
issn = {1875-5453 1389-2002},
year = {2021},
date = {2021-01-01},
journal = {Current drug metabolism},
volume = {22},
number = {8},
pages = {584–595},
abstract = {Polycyclic aromatic hydrocarbons (PAHs) represent a class of widely distributed environmental pollutants that have been primarily studied as genotoxic compounds. Their mutagenicity/genotoxicity largely depends on their oxidative metabolism leading to the production of dihydrodiol epoxide metabolites, as well as additional metabolites contributing to oxidative DNA damage, such as PAH quinones. However, both parental PAHs and their metabolites, including PAH quinones or hydroxylated PAHs, have been shown to produce various types of non-genotoxic effects. These include e.g., activation of the aryl hydrocarbon receptor and/or additional nuclear receptors, activation of membrane receptors, including tyrosine kinases and G-protein coupled receptors, or activation of intracellular signaling pathways, such as mitogen-activated protein kinases, Akt kinase and Ca(2+)-dependent signaling. These pathways may, together with the cellular DNA damage responses, modulate cell proliferation, cell survival or cell-to-cell communication, thus contributing to the known carcinogenic effects of PAHs. In the present review, we summarize some of the known non-genotoxic effects of PAHs, focusing primarily on those that have also been shown to be modulated by PAH metabolites. Despite the limitations of the available data, it seems evident that more attention should be paid to the discrimination between the potential non-genotoxic effects of parental PAHs and those of their metabolites. This may provide further insight into the mechanisms of toxicity of this large and diverse group of environmental pollutants.},
note = {Place: Netherlands},
keywords = {Activation, AhR, Animals, Benzo[a]pyrene, Cell Proliferation, Cell Survival, cell-to-cell communication, DNA Damage, Environmental Pollutants/*pharmacokinetics/*toxicity, Humans, Metabolic, Mutagens/*pharmacokinetics/*toxicity, oxidative stress, PAH metabolism., Polycyclic Aromatic Hydrocarbons/*pharmacokinetics/*toxicity},
pubstate = {published},
tppubtype = {article}
}
2020
Lenárt, Sára; Lenárt, Peter; Šmarda, Jan; Remšík, Ján; Souček, Karel; Beneš, Petr
Trop2: Jack of All Trades, Master of None. Journal Article
In: Cancers, vol. 12, no. 11, 2020, ISSN: 2072-6694, (Place: Switzerland).
Abstract | Links | BibTeX | Tags: cancer, epithelial-to-mesenchymal transition, metastases, proliferation, TACSTD2, therapy, Trop2
@article{lenart_trop2_2020,
title = {Trop2: Jack of All Trades, Master of None.},
author = {Sára Lenárt and Peter Lenárt and Jan Šmarda and Ján Remšík and Karel Souček and Petr Beneš},
doi = {10.3390/cancers12113328},
issn = {2072-6694},
year = {2020},
date = {2020-11-01},
journal = {Cancers},
volume = {12},
number = {11},
abstract = {Trophoblast cell surface antigen 2 (Trop2) is a widely expressed glycoprotein and an epithelial cell adhesion molecule (EpCAM) family member. Although initially identified as a transmembrane protein, other subcellular localizations and processed forms were described. Its congenital mutations cause a gelatinous drop-like corneal dystrophy, a disease characterized by loss of barrier function in corneal epithelial cells. Trop2 is considered a stem cell marker and its expression associates with regenerative capacity in various tissues. Trop2 overexpression was described in tumors of different origins; however, functional studies revealed both oncogenic and tumor suppressor roles. Nevertheless, therapeutic potential of Trop2 was recognized and clinical studies with drug-antibody conjugates have been initiated in various cancer types. One of these agents, sacituzumab govitecan, has been recently granted an accelerated approval for therapy of metastatic triple-negative breast cancer. In this article, we review the current knowledge about the yet controversial function of Trop2 in homeostasis and pathology.},
note = {Place: Switzerland},
keywords = {cancer, epithelial-to-mesenchymal transition, metastases, proliferation, TACSTD2, therapy, Trop2},
pubstate = {published},
tppubtype = {article}
}
Muresan, Ximena Maria; Bouchal, Jan; Culig, Zoran; Souček, Karel
Toll-Like Receptor 3 in Solid Cancer and Therapy Resistance. Journal Article
In: Cancers, vol. 12, no. 11, 2020, ISSN: 2072-6694, (Place: Switzerland).
Abstract | Links | BibTeX | Tags: cytokines, dsRNA, Metastasis, therapy resistance, toll-like receptor 3
@article{muresan_toll-like_2020,
title = {Toll-Like Receptor 3 in Solid Cancer and Therapy Resistance.},
author = {Ximena Maria Muresan and Jan Bouchal and Zoran Culig and Karel Souček},
doi = {10.3390/cancers12113227},
issn = {2072-6694},
year = {2020},
date = {2020-11-01},
journal = {Cancers},
volume = {12},
number = {11},
abstract = {Toll-like receptor 3 (TLR3) is a member of the TLR family, which has been extensively studied for its antiviral function. It is highly expressed in the endosomes of antigen-presenting immune cells and epithelial cells. TLR3 binds specifically double-strand RNAs (dsRNAs), leading to the activation of mainly two downstream pathways: the phosphorylation of IRF3, with subsequent production of type I interferon, and the activation of NF-κB, which drives the production of inflammatory cytokines and chemokines. Several studies have demonstrated TLR3 expression in multiple neoplasia types including breast, prostate, and lung cancer. Most studies were focused on the beneficial role of TLR3 activation in tumor cells, which leads to the production of cytotoxic cytokines and interferons and promotes caspase-dependent apoptosis. Indeed, ligands of this receptor were proposed for the treatment of cancer, also in combination with conventional chemotherapy. In contrast to these findings, recent evidence showed a link between TLR3 and tumor progression, metastasis, and therapy resistance. In the present review, we summarize the current knowledge of the mechanisms through which TLR3 can either lead to tumor regression or promote carcinogenesis as well as the potential of TLR-based therapies in resistant cancer.},
note = {Place: Switzerland},
keywords = {cytokines, dsRNA, Metastasis, therapy resistance, toll-like receptor 3},
pubstate = {published},
tppubtype = {article}
}
Vondráček, Jan; Pěnčíková, Kateřina; Ciganek, Miroslav; Pivnička, Jakub; Karasová, Martina; Hýžďalová, Martina; Strapáčová, Simona; Pálková, Lenka; Neča, Jiří; Matthews, Jason; Lom, Michal Vojtíšek; Topinka, Jan; Milcová, Alena; Machala, Miroslav
Environmental six-ring polycyclic aromatic hydrocarbons are potent inducers of the AhR-dependent signaling in human cells. Journal Article
In: Environmental pollution (Barking, Essex : 1987), vol. 266, no. Pt 2, pp. 115125, 2020, ISSN: 1873-6424 0269-7491, (Place: England).
Abstract | Links | BibTeX | Tags: *Polycyclic Aromatic Hydrocarbons, *Receptors, AhR, Anti-estrogenicity, Aryl Hydrocarbon, Carcinogenic PAHs, Genotoxicity, Humans, Lung cell toxicity, Particulate Matter, Signal Transduction, Vehicle Emissions
@article{vondracek_environmental_2020,
title = {Environmental six-ring polycyclic aromatic hydrocarbons are potent inducers of the AhR-dependent signaling in human cells.},
author = {Jan Vondráček and Kateřina Pěnčíková and Miroslav Ciganek and Jakub Pivnička and Martina Karasová and Martina Hýžďalová and Simona Strapáčová and Lenka Pálková and Jiří Neča and Jason Matthews and Michal Vojtíšek Lom and Jan Topinka and Alena Milcová and Miroslav Machala},
doi = {10.1016/j.envpol.2020.115125},
issn = {1873-6424 0269-7491},
year = {2020},
date = {2020-11-01},
journal = {Environmental pollution (Barking, Essex : 1987)},
volume = {266},
number = {Pt 2},
pages = {115125},
abstract = {The toxicities of many environmental polycyclic aromatic hydrocarbons (PAHs), in particular those of high-molecular-weight PAHs (with MW higher than 300), remain poorly characterized. The objective of this study was to evaluate the ability of selected environmentally relevant PAHs with MW 302 (MW302 PAHs) to activate the aryl hydrocarbon receptor (AhR), since this represents a major toxic mode of action of PAHs. A large number of the evaluated compounds exhibited strong AhR-mediated activities, in particular in human models. The studied MW302 PAHs also significantly contributed to the overall calculated AhR activities of complex environmental mixtures, including both defined standard reference materials and collected diesel exhaust particles. The high AhR-mediated activities of representative MW302 PAHs, e.g. naphtho[1,2-k]fluoranthene, corresponded with the modulation of expression of relevant AhR target genes in a human lung cell model, or with the AhR-dependent suppression of cell cycle progression/proliferation in estrogen-sensitive cells. This was in a marked contrast with the limited genotoxicity of the same compound(s). Given the substantial levels of the AhR-activating MW302 PAHs in combustion particles, it seems important to continue to investigate the toxic modes of action of this large group of PAHs associated with airborne particulate matter.},
note = {Place: England},
keywords = {*Polycyclic Aromatic Hydrocarbons, *Receptors, AhR, Anti-estrogenicity, Aryl Hydrocarbon, Carcinogenic PAHs, Genotoxicity, Humans, Lung cell toxicity, Particulate Matter, Signal Transduction, Vehicle Emissions},
pubstate = {published},
tppubtype = {article}
}
Drápela, Stanislav; Khirsariya, Prashant; Weerden, Wytske M.; Fedr, Radek; Suchánková, Tereza; Búzová, Diana; Červený, Jan; Hampl, Aleš; Puhr, Martin; Watson, William R.; Culig, Zoran; Krejčí, Lumír; Paruch, Kamil; Souček, Karel
In: Molecular oncology, vol. 14, no. 10, pp. 2487–2503, 2020, ISSN: 1878-0261 1574-7891, (Place: United States).
Abstract | Links | BibTeX | Tags: *Mitosis/drug effects, Animals, castration-resistant prostate cancer, Cell Death/drug effects, Cell Line, Cell Proliferation/drug effects, Checkpoint Kinase 1, Checkpoint Kinase 1/*antagonists & inhibitors/metabolism, Deoxycytidine/*analogs & derivatives/pharmacology, Docetaxel resistance, Docetaxel/*pharmacology, Drug resistance, gemcitabine, Humans, Male, Mice, mitotic catastrophe, MU380, Neoplasm/*drug effects, Piperidines/chemistry/*pharmacology, Prostatic Neoplasms/*pathology, Pyrazoles/chemistry/*pharmacology, Pyrimidines/chemistry/*pharmacology, S Phase/drug effects, SCID, Tumor, Xenograft Model Antitumor Assays
@article{drapela_chk1_2020,
title = {The CHK1 inhibitor MU380 significantly increases the sensitivity of human docetaxel-resistant prostate cancer cells to gemcitabine through the induction of mitotic catastrophe.},
author = {Stanislav Drápela and Prashant Khirsariya and Wytske M. Weerden and Radek Fedr and Tereza Suchánková and Diana Búzová and Jan Červený and Aleš Hampl and Martin Puhr and William R. Watson and Zoran Culig and Lumír Krejčí and Kamil Paruch and Karel Souček},
doi = {10.1002/1878-0261.12756},
issn = {1878-0261 1574-7891},
year = {2020},
date = {2020-10-01},
journal = {Molecular oncology},
volume = {14},
number = {10},
pages = {2487–2503},
abstract = {As treatment options for patients with incurable metastatic castration-resistant prostate cancer (mCRPC) are considerably limited, novel effective therapeutic options are needed. Checkpoint kinase 1 (CHK1) is a highly conserved protein kinase implicated in the DNA damage response (DDR) pathway that prevents the accumulation of DNA damage and controls regular genome duplication. CHK1 has been associated with prostate cancer (PCa) induction, progression, and lethality; hence, CHK1 inhibitors SCH900776 (also known as MK-8776) and the more effective SCH900776 analog MU380 may have clinical applications in the therapy of PCa. Synergistic induction of DNA damage with CHK1 inhibition represents a promising therapeutic approach that has been tested in many types of malignancies, but not in chemoresistant mCRPC. Here, we report that such therapeutic approach may be exploited using the synergistic action of the antimetabolite gemcitabine (GEM) and CHK1 inhibitors SCH900776 and MU380 in docetaxel-resistant (DR) mCRPC. Given the results, both CHK1 inhibitors significantly potentiated the sensitivity to GEM in a panel of chemo-naïve and matched DR PCa cell lines under 2D conditions. MU380 exhibited a stronger synergistic effect with GEM than clinical candidate SCH900776. MU380 alone or in combination with GEM significantly reduced spheroid size and increased apoptosis in all patient-derived xenograft 3D cultures, with a higher impact in DR models. Combined treatment induced premature mitosis from G1 phase resulting in the mitotic catastrophe as a prestage of apoptosis. Finally, treatment by MU380 alone, or in combination with GEM, significantly inhibited tumor growth of both PC339-DOC and PC346C-DOC xenograft models in mice. Taken together, our data suggest that metabolically robust and selective CHK1 inhibitor MU380 can bypass docetaxel resistance and improve the effectiveness of GEM in DR mCRPC models. This approach might allow for dose reduction of GEM and thereby minimize undesired toxicity and may represent a therapeutic option for patients with incurable DR mCRPC.},
note = {Place: United States},
keywords = {*Mitosis/drug effects, Animals, castration-resistant prostate cancer, Cell Death/drug effects, Cell Line, Cell Proliferation/drug effects, Checkpoint Kinase 1, Checkpoint Kinase 1/*antagonists & inhibitors/metabolism, Deoxycytidine/*analogs & derivatives/pharmacology, Docetaxel resistance, Docetaxel/*pharmacology, Drug resistance, gemcitabine, Humans, Male, Mice, mitotic catastrophe, MU380, Neoplasm/*drug effects, Piperidines/chemistry/*pharmacology, Prostatic Neoplasms/*pathology, Pyrazoles/chemistry/*pharmacology, Pyrimidines/chemistry/*pharmacology, S Phase/drug effects, SCID, Tumor, Xenograft Model Antitumor Assays},
pubstate = {published},
tppubtype = {article}
}
Procházková, Jiřina; Slavík, Josef; Bouchal, Jan; Levková, Monika; Hušková, Zlata; Ehrmann, Jiří; Ovesná, Petra; Kolář, Zdeněk; Skalický, Pavel; Straková, Nicol; Zapletal, Ondřej; Kozubík, Alois; Hofmanová, Jiřina; Vondráček, Jan; Machala, Miroslav
Specific alterations of sphingolipid metabolism identified in EpCAM-positive cells isolated from human colon tumors. Journal Article
In: Biochimica et biophysica acta. Molecular and cell biology of lipids, vol. 1865, no. 9, pp. 158742, 2020, ISSN: 1879-2618 1388-1981, (Place: Netherlands).
Links | BibTeX | Tags: 80 and over, Adult, Aged, B4GALTs, Colon adenocarcinoma, Colorectal Neoplasms/*metabolism, EPCAM-positive cells, Epithelial Cell Adhesion Molecule/*metabolism, Female, Galactosyltransferases/genetics, Humans, Lactosylceramide, Male, Middle Aged, Sphingolipid metabolism, Sphingolipids/*metabolism
@article{prochazkova_specific_2020,
title = {Specific alterations of sphingolipid metabolism identified in EpCAM-positive cells isolated from human colon tumors.},
author = {Jiřina Procházková and Josef Slavík and Jan Bouchal and Monika Levková and Zlata Hušková and Jiří Ehrmann and Petra Ovesná and Zdeněk Kolář and Pavel Skalický and Nicol Straková and Ondřej Zapletal and Alois Kozubík and Jiřina Hofmanová and Jan Vondráček and Miroslav Machala},
doi = {10.1016/j.bbalip.2020.158742},
issn = {1879-2618 1388-1981},
year = {2020},
date = {2020-09-01},
journal = {Biochimica et biophysica acta. Molecular and cell biology of lipids},
volume = {1865},
number = {9},
pages = {158742},
note = {Place: Netherlands},
keywords = {80 and over, Adult, Aged, B4GALTs, Colon adenocarcinoma, Colorectal Neoplasms/*metabolism, EPCAM-positive cells, Epithelial Cell Adhesion Molecule/*metabolism, Female, Galactosyltransferases/genetics, Humans, Lactosylceramide, Male, Middle Aged, Sphingolipid metabolism, Sphingolipids/*metabolism},
pubstate = {published},
tppubtype = {article}
}
Remšík, Ján; Pícková, Markéta; Vacek, Ondřej; Fedr, Radek; Binó, Lucia; Hampl, Aleš; Souček, Karel
TGF-β regulates Sca-1 expression and plasticity of pre-neoplastic mammary epithelial stem cells. Journal Article
In: Scientific reports, vol. 10, no. 1, pp. 11396, 2020, ISSN: 2045-2322, (Place: England).
Abstract | Links | BibTeX | Tags: Animal/pathology, Animals, Ataxin-1/*metabolism, Breast Neoplasms/genetics/*pathology, Cell Line, Cell Plasticity/genetics, Epithelial Cells/pathology, Epithelial-Mesenchymal Transition/genetics, ErbB-2/genetics, Experimental/genetics/*pathology, Female, Gene Expression Regulation, Humans, Mammary Glands, Mammary Neoplasms, Mice, Neoplastic, Neoplastic Stem Cells/*pathology, Receptor, Recombinant Proteins/genetics/metabolism, Signal Transduction/genetics, Transforming Growth Factor beta/genetics/*metabolism, Tumor/transplantation
@article{remsik_tgf-_2020,
title = {TGF-β regulates Sca-1 expression and plasticity of pre-neoplastic mammary epithelial stem cells.},
author = {Ján Remšík and Markéta Pícková and Ondřej Vacek and Radek Fedr and Lucia Binó and Aleš Hampl and Karel Souček},
doi = {10.1038/s41598-020-67827-4},
issn = {2045-2322},
year = {2020},
date = {2020-07-01},
journal = {Scientific reports},
volume = {10},
number = {1},
pages = {11396},
abstract = {The epithelial-mesenchymal plasticity, in tight association with stemness, contributes to the mammary gland homeostasis, evolution of early neoplastic lesions and cancer dissemination. Focused on cell surfaceome, we used mouse models of pre-neoplastic mammary epithelial and cancer stem cells to reveal the connection between cell surface markers and distinct cell phenotypes. We mechanistically dissected the TGF-β family-driven regulation of Sca-1, one of the most commonly used adult stem cell markers. We further provided evidence that TGF-β disrupts the lineage commitment and promotes the accumulation of tumor-initiating cells in pre-neoplastic cells.},
note = {Place: England},
keywords = {Animal/pathology, Animals, Ataxin-1/*metabolism, Breast Neoplasms/genetics/*pathology, Cell Line, Cell Plasticity/genetics, Epithelial Cells/pathology, Epithelial-Mesenchymal Transition/genetics, ErbB-2/genetics, Experimental/genetics/*pathology, Female, Gene Expression Regulation, Humans, Mammary Glands, Mammary Neoplasms, Mice, Neoplastic, Neoplastic Stem Cells/*pathology, Receptor, Recombinant Proteins/genetics/metabolism, Signal Transduction/genetics, Transforming Growth Factor beta/genetics/*metabolism, Tumor/transplantation},
pubstate = {published},
tppubtype = {article}
}