Latest Publications

@article{andrysik_aryl_2013,

title = {Aryl hydrocarbon receptor-mediated disruption of contact inhibition is associated with connexin43 downregulation and inhibition of gap junctional intercellular communication.},

author = {Zdeněk Andrysík and Jiřina Procházková and Markéta Kabátková and Lenka Umannová and Pavlína Simečková and Jiří Kohoutek and Alois Kozubík and Miroslav Machala and Jan Vondráček},

doi = {10.1007/s00204-012-0963-7},

issn = {1432-0738 0340-5761},

year  = {2013},

date = {2013-03-01},

journal = {Archives of toxicology},

volume = {87},

number = {3},

pages = {491–503},

abstract = {The aryl hydrocarbon receptor (AhR) contributes to the control of cell-to-cell communication, cell adhesion, migration or proliferation. In the present study, we investigated the regulation of connexin43 (Cx43) and Cx43-mediated gap junctional intercellular communication (GJIC) during the AhR-dependent disruption of contact inhibition in non-tumorigenic liver epithelial cells. The contact inhibition of cell proliferation is a process restricting the cell division of confluent non-transformed cells, which is frequently abolished in cancer cells; however, the mechanisms contributing to its disruption are still only partially understood. Disruption of contact inhibition, which was induced by toxic AhR ligands 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or polycyclic aromatic hydrocarbons in epithelial WB-F344 cells, reduced Cx43 protein levels, possibly via enhanced proteasomal degradation, significantly decreased the amount of gap junction plaques and downregulated GJIC, in an AhR-dependent manner. Although both intracellular and membrane Cx43 pools were markedly reduced in cells released from contact inhibition by TCDD, siRNA-mediated Cx43 knock-down was not sufficient to stimulate proliferation in contact-inhibited cells. Our data suggest that downregulation of Cx43/GJIC in non-transformed epithelial cells is an inherent part of disruption of contact inhibition, which occurs at the post-transcriptional level. This process runs in parallel with alterations of other forms of cell-to-cell communication, thus suggesting that toxic AhR agonists may simultaneously abrogate contact inhibition and reduce GJIC, two essential mechanisms linked to deregulation of cell-to-cell communication during tumor promotion and progression.},

note = {Place: Germany},

keywords = {Animals, Aryl Hydrocarbon/*agonists/genetics/metabolism, Benz(a)Anthracenes/toxicity, Carcinogens/*toxicity, Cell Communication/*drug effects, Cell Line, Cell Proliferation, Cell Transformation, Connexin 43/genetics/*metabolism, Contact Inhibition/*drug effects, Dose-Response Relationship, Down-Regulation, Drug, Epithelial Cells/*drug effects/metabolism/pathology, Fluorenes/toxicity, Gap Junctions/*drug effects/metabolism/pathology, Gene Knockdown Techniques, Indoles/pharmacology, Ligands, Liver Neoplasms/chemically induced/metabolism/pathology, Liver/*drug effects/metabolism/pathology, Neoplastic/chemically induced/metabolism/pathology, Phloroglucinol/analogs & derivatives/pharmacology, Phosphorylation, Polychlorinated Dibenzodioxins/toxicity, Proteasome Endopeptidase Complex/metabolism, Rats, Receptors, RNA Interference, Signal Transduction/*drug effects, Time Factors, Transfection},

pubstate = {published},

tppubtype = {article}

}

@article{starsichova_tgf-1_2012,

title = {TGF-β1 signaling plays a dominant role in the crosstalk between TGF-β1 and the aryl hydrocarbon receptor ligand in prostate epithelial cells.},

author = {Andrea Staršíchová and Eva Hrubá and Eva Slabáková and Zuzana Pernicová and Jiřina Procházková and Kateřina Pěnčíková and Václav Seda and Markéta Kabátková and Jan Vondráček and Alois Kozubík and Miroslav Machala and Karel Souček},

doi = {10.1016/j.cellsig.2012.04.008},

issn = {1873-3913 0898-6568},

year  = {2012},

date = {2012-08-01},

journal = {Cellular signalling},

volume = {24},

number = {8},

pages = {1665–1676},

abstract = {Crosstalk between the aryl hydrocarbon receptor (AhR) and transforming growth factor-β1 (TGF-β1) signaling has been observed in various experimental models. However, both molecular mechanism underlying this crosstalk and tissue-specific context of this interaction are still only partially understood. In a model of human non-tumorigenic prostate epithelial cells BPH-1, derived from the benign prostatic hyperplasia, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) persistently activates the AhR signaling pathway and induces expression of xenobiotic metabolizing enzymes, such as CYP1A1 or CYP1B1. Here we demonstrate that TGF-β1 suppresses the AhR-mediated gene expression through multiple mechanisms, involving inhibition of AhR expression and down-regulation of nuclear AhR, via a SMAD4-dependent pathway. In contrast, TCDD-induced AhR signaling does not affect either TGF-β1-regulated gene expression or epithelial-to-mesenchymal transition. These observations suggest that, in the context of prostate epithelium, TGF-β1 signaling plays a dominant role in the crosstalk with AhR signaling pathway. Given the importance of TGF-β1 signaling in regulation of prostate epithelial tissue homeostasis, as well as the recently revealed role of AhR in prostate development and tumorigenesis, the above findings contribute to our understanding of the mechanisms underlying the crosstalk between the two signaling pathways in the prostate-specific context.},

note = {Place: England},

keywords = {Aryl Hydrocarbon/antagonists & inhibitors/genetics/metabolism, Cells, Cultured, Epithelial Cells/*drug effects/*metabolism, Humans, Ligands, Male, Polychlorinated Dibenzodioxins/*pharmacology, Prostate/*cytology, Receptors, Recombinant Proteins/metabolism, Signal Transduction/*drug effects, Transforming Growth Factor beta1/genetics/*metabolism},

pubstate = {published},

tppubtype = {article}

}

@article{ondrouskova_alternative_2008,

title = {Alternative pathways of programmed cell death are activated in cells with defective caspase-dependent apoptosis.},

author = {Eva Ondrousková and Karel Soucek and Viktor Horváth and Jan Smarda},

doi = {10.1016/j.leukres.2007.05.012},

issn = {0145-2126},

year  = {2008},

date = {2008-04-01},

journal = {Leukemia research},

volume = {32},

number = {4},

pages = {599–609},

abstract = {Loss of programmed cell death pathways is one of the features of malignancy that complicate the response of cancer cells to a therapy. Activation of alternative cell death pathways offers a promising approach to enhance efficiency of cancer chemotherapy. We analysed programmed cell death pathways of v-myb-transformed BM2 monoblasts induced by arsenic trioxide, cycloheximide and camptothecin with U937 promonocytes as a reference cell line. We show that induced death of BM2 cells is not executed by caspases but rather by alternative cell death pathways. Camptothecin induces the lysosome-dependent cell death, arsenic trioxide induces autophagy, and most of cycloheximide-treated BM2 cells die by necrosis. The fact that alternative cell death pathways can be switched in cells with defects in activation and/or function of caspases suggests that understanding and targeting of these pathways could improve therapy of cancer cells suffering from defective apoptosis.},

note = {Place: England},

keywords = {Animals, Antineoplastic Agents/*pharmacology, Apoptosis/*drug effects, Arsenic Trioxide, Arsenicals/pharmacology, Autophagy/*drug effects, Blotting, Camptothecin/pharmacology, Caspases/*metabolism, Cell Line, Cell Transformation, Chickens, Cycloheximide/pharmacology, Fluorescence, Genes, Humans, Microscopy, myb/physiology, Necrosis, Neoplastic/*pathology, Oxides/pharmacology, Signal Transduction/*drug effects, Transformed, U937 Cells/drug effects, Western},

pubstate = {published},

tppubtype = {article}

}

@article{machala_inhibition_2003,

title = {Inhibition of gap junctional intercellular communication by noncoplanar polychlorinated biphenyls: inhibitory potencies and screening for potential mode(s) of action.},

author = {Miroslav Machala and Ludek Bláha and Jan Vondrácek and James E. Trosko and Jacob Scott and Brad L. Upham},

doi = {10.1093/toxsci/kfg209},

issn = {1096-6080 1096-0929},

year  = {2003},

date = {2003-11-01},

journal = {Toxicological sciences : an official journal of the Society of Toxicology},

volume = {76},

number = {1},

pages = {102–111},

abstract = {Polychlorinated biphenyls (PCBs), a structurally diverse group of environmental pollutants, are effective promoters in two-stage cancer models, which implies that epigenetic mechanisms are involved. Inhibition of gap junctional intercellular communication (GJIC) belongs among critical epigenetic events of tumor promotion. We determined the relative potencies of a series of environmentally relevant PCB congeners to inhibit GJIC in vitro in a rat liver epithelial cell line with pluripotent oval cell characteristics. The nonplanar PCBs were potent inhibitors of GJIC, whereas the coplanar PCBs did not inhibit GJIC. We then compared the effects of the coplanar PCB 126 (3,3',4,4',5-pentachlorobiphenyl) and the noncoplanar PCB 153 (2,2',4,4',5,5'-hexachlorobiphenyl) with effects of two model GJIC inhibitors, a tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) and epidermal growth factor (EGF). In contrast to TPA or EGF, PCB 153 elicited a long-term downregulation of GJIC (up to 48 h). Using Western blot analysis with phospho-specific antibodies, it was found that PCB 153, and not PCB 126, activated mitogen-activated protein kinases ERK1/2; however in contrast to TPA and EGF, this activation was observed at the time points subsequent to GJIC inhibition. Moreover, blocking of ERK1/2 activation did not prevent the GJIC inhibition induced by PCB 153. Therefore, additional intracellular signaling pathways potentially involved in the downregulation of GJIC by PCBs were screened by using specific chemical probes inhibiting serine/threonine kinases, tyrosine kinases, and phospholipases. The inhibition of diacylglycerol lipase partially blocked and the selective inhibition of Src kinases and phosphatidylcholine-specific phospholipase C (PC-PLC) completely blocked the inhibitory effects of the noncoplanar PCB on GJIC, indicating that PC-PLC or sphingomyelinase and Src might be upstream regulators of noncoplanar PCB-induced inhibition of GJIC.},

note = {Place: United States},

keywords = {Animals, Blotting, Cell Line, Epidermal Growth Factor/toxicity, Epithelial Cells/drug effects/enzymology, Gap Junctions/*drug effects/enzymology, Liver/cytology, Mitogen-Activated Protein Kinases/metabolism, Polychlorinated Biphenyls/*toxicity, Rats, Signal Transduction/*drug effects, Sphingomyelin Phosphodiesterase/metabolism, src-Family Kinases/metabolism, Tetradecanoylphorbol Acetate/toxicity, Western},

pubstate = {published},

tppubtype = {article}

}