Aryl hydrocarbon receptor-mediated disruption of contact inhibition is associated with connexin43 downregulation and inhibition of gap junctional intercellular communication
Autor: | Zdeněk Andrysík, Lenka Umannová, Markéta Kabátková, Jiřina Procházková, Jan Vondráček, Jiří Kohoutek, Pavlína Šimečková, Alois Kozubík, Miroslav Machala |
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Rok vydání: | 2012 |
Předmět: |
Proteasome Endopeptidase Complex
Indoles Polychlorinated Dibenzodioxins Time Factors Cell division Health Toxicology and Mutagenesis Down-Regulation Cell Communication Phloroglucinol Ligands Transfection Toxicology Cell Line Downregulation and upregulation Benz(a)Anthracenes Animals Phosphorylation Cell adhesion Cell Proliferation Fluorenes Dose-Response Relationship Drug biology Contact Inhibition Cell growth Liver Neoplasms Gap Junctions Contact inhibition Epithelial Cells General Medicine Aryl hydrocarbon receptor Rats Cell biology Cell Transformation Neoplastic Liver Receptors Aryl Hydrocarbon Connexin 43 Gene Knockdown Techniques Cancer cell Carcinogens biology.protein RNA Interference Intracellular Signal Transduction |
Zdroj: | Archives of Toxicology. 87:491-503 |
ISSN: | 1432-0738 0340-5761 |
Popis: | 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. |
Databáze: | OpenAIRE |
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