title: Aryl hydrocarbon receptor-mediated disruption of contact inhibition is associated with connexin43 downregulation and inhibition of gap junctional intercellular communication.
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.
authors.affiliation: Department of Cytokinetics, Institute of Biophysics, Academy of Sciences of the Czech Republic, Královopolská 135, 61265, Brno, Czech Republic.
authors.forename: Zdeněk
authors.initials: Z
authors.lastname: Andrysík
authors.forename: Jiřina
authors.initials: J
authors.lastname: Procházková
authors.forename: Markéta
authors.initials: M
authors.lastname: Kabátková
authors.forename: Lenka
authors.initials: L
authors.lastname: Umannová
authors.forename: Pavlína
authors.initials: P
authors.lastname: Simečková
authors.forename: Jiří
authors.initials: J
authors.lastname: Kohoutek
authors.forename: Alois
authors.initials: A
authors.lastname: Kozubík
authors.forename: Miroslav
authors.initials: M
authors.lastname: Machala
authors.forename: Jan
authors.initials: J
authors.lastname: Vondráček
mesh_terms: D000818:Animals; D001551:Benz(a)Anthracenes / Q000633:toxicity; D002273:Carcinogens / Q000633:toxicity*; D002450:Cell Communication / Q000187:drug effects*; D002460:Cell Line; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism*; D003260:Contact Inhibition / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005449:Fluorenes / Q000633:toxicity; D017629:Gap Junctions / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D055785:Gene Knockdown Techniques; D007211:Indoles / Q000494:pharmacology; D008024:Ligands; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D010696:Phloroglucinol / Q000031:analogs & derivatives / Q000494:pharmacology; D010766:Phosphorylation; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D014162:Transfection
chemical_list: D001551:Benz(a)Anthracenes; D002273:Carcinogens; D018031:Connexin 43; D005449:Fluorenes; C580592:Gja1 protein, rat; C411652:IC 261; D007211:Indoles; D008024:Ligands; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; C007738:fluoranthene; C030935:benz(a)anthracene; D010696:Phloroglucinol; D046988:Proteasome Endopeptidase Complex; C006703:benzo(b)fluoranthene