Inhibition of apoptosis by the ligands of the aryl hydrocarbon receptor (AhR) has been proposed to play a role in their tumor promoting effects on liver parenchymal cells. However, little is presently known about the impact of toxic AhR ligands, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on apoptosis in other liver cell types, such as in liver epithelial/progenitor cells. In the present study, we focused on the effects of TCDD on apoptosis regulation in a model of liver progenitor cells, rat WB-F344 cell line, during the TCDD-elicited release from contact inhibition. The stimulation of cell proliferation in this cell line was associated with deregulated expression of a number of genes known to be under transcriptional control of the Hippo signaling pathway, a principal regulatory pathway involved in contact inhibition of cell proliferation. Interestingly, we found that mRNA and protein levels of survivin, a known Hippo target, which plays a role both in cell division and inhibition of apoptosis, were significantly up-regulated in rat liver epithelial cell model, as well as in undifferentiated human liver HepaRG cells. Using the short interfering RNA-mediated knockdown, we confirmed that survivin plays a central role in cell division of WB-F344 cells. When evaluating the effects of TCDD on apoptosis induction by camptothecin, a genotoxic topoisomerase I inhibitor, we observed that the pre-treatment of WB-F344 cells with TCDD increased number of cells with apoptotic nuclear morphology, and it potentiated cleavage of both caspase-3 and poly(ADP-ribose) polymerase I. This indicated that despite the observed up-regulation of survivin, apoptosis induced by the genotoxin was potentiated in the model of rat liver progenitor cells. The present results indicate that, unlike in hepatocytes, AhR agonists may not prevent induction of apoptosis elicited by DNA-damaging agents in a model of rat liver progenitor cells.
- MeSH
- apoptóza účinky léků MeSH
- buněčné linie MeSH
- časové faktory MeSH
- epitelové buňky účinky léků metabolismus patologie MeSH
- genetická transkripce účinky léků MeSH
- inhibitory apoptózy genetika metabolismus MeSH
- inhibitory topoisomerasy I toxicita MeSH
- játra účinky léků metabolismus patologie MeSH
- kamptothecin toxicita MeSH
- kaspasa 3 metabolismus MeSH
- kontaktní inhibice účinky léků MeSH
- lidé MeSH
- poly(ADP-ribosa)-polymerasy metabolismus MeSH
- polychlorované dibenzodioxiny toxicita MeSH
- potkani inbrední F344 MeSH
- proteiny asociované s mikrotubuly genetika metabolismus MeSH
- receptory aromatických uhlovodíků agonisté metabolismus MeSH
- RNA interference MeSH
- signální transdukce účinky léků MeSH
- transfekce MeSH
- transkripční faktory bHLH agonisté metabolismus MeSH
- upregulace MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
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.
- MeSH
- benz(a)anthraceny toxicita MeSH
- buněčné linie MeSH
- časové faktory MeSH
- down regulace MeSH
- epitelové buňky účinky léků metabolismus patologie MeSH
- floroglucinol analogy a deriváty farmakologie MeSH
- fluoreny toxicita MeSH
- fosforylace MeSH
- genový knockdown MeSH
- indoly farmakologie MeSH
- játra účinky léků metabolismus patologie MeSH
- karcinogeny toxicita MeSH
- konexin 43 genetika metabolismus MeSH
- kontaktní inhibice účinky léků MeSH
- krysa rodu rattus MeSH
- ligandy MeSH
- mezerový spoj účinky léků metabolismus patologie MeSH
- mezibuněčná komunikace účinky léků MeSH
- nádorová transformace buněk chemicky indukované metabolismus patologie MeSH
- nádory jater chemicky indukované metabolismus patologie MeSH
- polychlorované dibenzodioxiny toxicita MeSH
- proliferace buněk MeSH
- proteasomový endopeptidasový komplex metabolismus MeSH
- receptory aromatických uhlovodíků agonisté genetika metabolismus MeSH
- RNA interference MeSH
- signální transdukce účinky léků MeSH
- transfekce MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- brýle MeSH
- corpus ciliare patologie MeSH
- epitel patologie MeSH
- epitelové buňky MeSH
- fibroblasty patologie MeSH
- iris patologie MeSH
- kontaktní inhibice MeSH
- kultivované buňky MeSH
- lidé MeSH
- makrofágy patologie MeSH
- melanocyty patologie MeSH
- melanom patologie MeSH
- mikroskopie fázově kontrastní MeSH
- nádory choroidey patologie MeSH
- nádory oka patologie MeSH
- pohyb buněk MeSH
- skot MeSH
- uvea patologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- skot MeSH
- zvířata MeSH
- MeSH
- antigeny MeSH
- buněčná membrána imunologie MeSH
- buněčné linie MeSH
- buňky kostní dřeně MeSH
- genotyp MeSH
- histocytochemie MeSH
- histokompatibilita MeSH
- imunogenetika MeSH
- kontaktní inhibice MeSH
- kostní dřeň imunologie účinky záření MeSH
- kultivační média MeSH
- kultivační techniky MeSH
- myši MeSH
- pohyb buněk MeSH
- radiační účinky MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
