Latest Publications

@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}

}

@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}

}

@article{pernicova_role_2014,

title = {The role of high cell density in the promotion of neuroendocrine transdifferentiation of prostate cancer cells.},

author = {Zuzana Pernicová and Eva Slabáková and Radek Fedr and Šárka Šimečková and Josef Jaroš and Tereza Suchánková and Jan Bouchal and Gvantsa Kharaishvili and Milan Král and Alois Kozubík and Karel Souček},

doi = {10.1186/1476-4598-13-113},

issn = {1476-4598},

year  = {2014},

date = {2014-05-01},

journal = {Molecular cancer},

volume = {13},

pages = {113},

abstract = {BACKGROUND: Tumor heterogeneity and the plasticity of cancer cells present challenges for effective clinical diagnosis and therapy. Such challenges are epitomized by neuroendocrine transdifferentiation (NED) and the emergence of neuroendocrine-like cancer cells in prostate tumors. This phenomenon frequently arises from androgen-depleted prostate adenocarcinoma and is associated with the development of castration-resistant prostate cancer and poor prognosis. RESULTS: In this study, we showed that NED was evoked in both androgen receptor (AR)-positive and AR-negative prostate epithelial cell lines by growing the cells to a high density. Androgen depletion and high-density cultivation were both associated with cell cycle arrest and deregulated expression of several cell cycle regulators, such as p27Kip1, members of the cyclin D protein family, and Cdk2. Dual inhibition of Cdk1 and Cdk2 using pharmacological inhibitor or RNAi led to modulation of the cell cycle and promotion of NED. We further demonstrated that the cyclic adenosine 3', 5'-monophosphate (cAMP)-mediated pathway is activated in the high-density conditions. Importantly, inhibition of cAMP signaling using a specific inhibitor of adenylate cyclase, MDL-12330A, abolished the promotion of NED by high cell density. CONCLUSIONS: Taken together, our results imply a new relationship between cell cycle attenuation and promotion of NED and suggest high cell density as a trigger for cAMP signaling that can mediate reversible NED in prostate cancer cells.},

note = {Place: England},

keywords = {*Cell Transdifferentiation/drug effects, Androgen/metabolism, Androgens/pharmacology, CDC2 Protein Kinase, Cell Count, Cell Cycle Checkpoints/drug effects, Cell Line, Cyclic AMP/metabolism, Cyclin-Dependent Kinase 2/metabolism, Cyclin-Dependent Kinases/metabolism, Epithelial Cells/drug effects/enzymology/pathology, Humans, Immunohistochemistry, Male, Neuroendocrine Cells/drug effects/*pathology, Prostatic Neoplasms/*pathology, Protein Kinase Inhibitors/pharmacology, Receptors, Signal Transduction/drug effects, Tumor},

pubstate = {published},

tppubtype = {article}

}

@article{kummer_estrogenic_2008,

title = {Estrogenic activity of environmental polycyclic aromatic hydrocarbons in uterus of immature Wistar rats.},

author = {Vladimír Kummer and Jarmila Masková and Zdenek Zralý and Jirí Neca and Pavlína Simecková and Jan Vondrácek and Miroslav Machala},

doi = {10.1016/j.toxlet.2008.06.862},

issn = {0378-4274},

year  = {2008},

date = {2008-08-01},

journal = {Toxicology letters},

volume = {180},

number = {3},

pages = {212–221},

abstract = {Polycyclic aromatic hydrocarbons (PAHs) are an important group of environmental pollutants, known for their mutagenic and carcinogenic activities. Many PAHs are aryl hydrocarbon receptor (AhR) ligands and several recent studies have suggested that PAHs or their metabolites may activate estrogen receptors (ER). The present study investigated possible estrogenic/antiestrogenic effects of abundant environmental contaminants benzo[a]pyrene (BaP), benz[a]anthracene (BaA), fluoranthene (Fla) and benzo[k]fluoranthene (BkF) in vivo, using the immature rat uterotrophic assay. The present results suggest that BaA, BaP and Fla behaved as estrogen-like compounds in immature Wistar rats, when applied for 3 consecutive days at 10mg/kg/day, as documented by a significant increase of uterine weight and hypertrophy of luminal epithelium. These effects were likely to be mediated by ERalpha, a major subtype of ER present in uterus, as they were inhibited by treatment with ER antagonist ICI 182,780. BaA, the most potent of studied PAHs, induced a significant estrogenic effect within a concentration range 0.1-50mg/kg/day; however, it did not reach the maximum level induced by reference estrogens. The proposed antiestrogenicity of the potent AhR agonist BkF was not confirmed in the present in vivo study; the exposure to BkF did not significantly affect the uterine weight, although a weak suppression of ERalpha immunostaining was observed in luminal and glandular epithelium, possibly related to its AhR-mediated activity. The PAHs under study did not induce marked genotoxic damage in uterine tissues, as documented by the lack of Ser-15-phoshorylated p53 protein staining. With the exception of Fla, all three remaining compounds increased CYP1-dependent monooxygenation activities in liver at the doses used, suggesting that the potential tissue-specific antiestrogenic effects of PAHs mediated by metabolization of 17beta-estradiol also cannot be excluded. Taken together, these environmentally relevant PAHs induced estrogenic effects in vivo, which might affect their toxic impact and carcinogenicity.},

note = {Place: Netherlands},

keywords = {Animals, Cytochrome P-450 CYP1A1/metabolism, Endocrine Disruptors/*toxicity, Environmental Pollutants/*toxicity, Epithelium/drug effects, Estradiol/metabolism, Estrogen Receptor alpha/metabolism, Estrogens/*biosynthesis, Female, Hydroxylation, Immunohistochemistry, Liver/drug effects/metabolism, Microsomes, Organ Size/drug effects, Ovary/drug effects, Phosphorylation, Polycyclic Aromatic Hydrocarbons/*toxicity, Rats, Tumor Suppressor Protein p53/metabolism, Uterus/drug effects/*metabolism, Wistar},

pubstate = {published},

tppubtype = {article}

}