The aryl hydrocarbon receptor-dependent disruption of contact inhibition in rat liver WB-F344 epithelial cells is linked with induction of survivin, but not with inhibition of apoptosis
Language English Country Ireland Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
25843524
DOI
10.1016/j.tox.2015.04.001
PII: S0300-483X(15)00063-3
Knihovny.cz E-resources
- Keywords
- AhR, Apoptosis, BIRC5/survivin, Contact inhibition, Hippo signaling, TCDD,
- MeSH
- Apoptosis drug effects MeSH
- Cell Line MeSH
- Time Factors MeSH
- Epithelial Cells drug effects metabolism pathology MeSH
- Transcription, Genetic drug effects MeSH
- Inhibitor of Apoptosis Proteins genetics metabolism MeSH
- Topoisomerase I Inhibitors toxicity MeSH
- Liver drug effects metabolism pathology MeSH
- Camptothecin toxicity MeSH
- Caspase 3 metabolism MeSH
- Contact Inhibition drug effects MeSH
- Humans MeSH
- Poly (ADP-Ribose) Polymerase-1 MeSH
- Poly(ADP-ribose) Polymerases metabolism MeSH
- Polychlorinated Dibenzodioxins toxicity MeSH
- Rats, Inbred F344 MeSH
- Microtubule-Associated Proteins genetics metabolism MeSH
- Receptors, Aryl Hydrocarbon agonists metabolism MeSH
- RNA Interference MeSH
- Signal Transduction drug effects MeSH
- Survivin MeSH
- Transfection MeSH
- Basic Helix-Loop-Helix Transcription Factors agonists metabolism MeSH
- Up-Regulation MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Ahr protein, rat MeSH Browser
- BIRC5 protein, human MeSH Browser
- Birc5 protein, rat MeSH Browser
- Casp3 protein, rat MeSH Browser
- Inhibitor of Apoptosis Proteins MeSH
- Topoisomerase I Inhibitors MeSH
- Camptothecin MeSH
- Caspase 3 MeSH
- Parp1 protein, rat MeSH Browser
- Poly (ADP-Ribose) Polymerase-1 MeSH
- Poly(ADP-ribose) Polymerases MeSH
- Polychlorinated Dibenzodioxins MeSH
- Microtubule-Associated Proteins MeSH
- Receptors, Aryl Hydrocarbon MeSH
- Survivin MeSH
- Basic Helix-Loop-Helix Transcription Factors MeSH
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.
Department of Chemistry and Toxicology Veterinary Research Institute 62100 Brno Czech Republic
Department of Cytokinetics Institute of Biophysics AS CR 61265 Brno Czech Republic
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