The antiapoptotic role of pregnane X receptor in human colon cancer cells.
The orphan nuclear receptor pregnane X receptor (PXR) plays an important role in the detoxification of foreign and endogenous chemicals, including bile acids. PXR promotes bile acid elimination by activating bile acid-detoxifying enzymes and transporters. Certain bile acids are known to promote colonic carcinogenesis by inducing colon cancer cell apoptosis. However, whether and how PXR plays a role in colon cancer apoptosis has not been reported. In this study, we showed that activation of PXR by genetic (using a constitutively activated PXR) or pharmacological (using PXR agonist rifampicin) means protected the PXR-overexpressing colon cancer HCT116 cells from deoxycholic acid-induced apoptosis. Interestingly, activation of PXR also protected HCT116 cells from adriamycin-induced cell death, suggesting that the antiapoptotic effect of PXR was not bile acid specific. Moreover, the antiapoptotic effect of PXR in HCT116 cells appeared to be independent of xenobiotic enzyme regulation, because these cells had little basal and inducible expression of bile acid-detoxifying enzymes. Instead, SuperArray analysis showed that PXR-mediated deoxycholic acid resistance was associated with up-regulation of multiple antiapoptotic genes, including BAG3, BIRC2, and MCL-1, and down-regulation of proapoptotic genes, such as BAK1 and TP53/p53. Treatment with rifampicin in colon cancer LS180 cells, a cell line known to express endogenous PXR, also inhibited apoptosis. Activation of PXR in transgenic mice inhibited bile acid-induced colonic epithelial apoptosis and sensitized mice to dimethylhydrazine-induced colonic carcinogenesis, suggesting that the antiapoptotic effect of PXR is conserved in normal colon epithelium. In summary, our results have established the antiapoptotic role of PXR in both human colon cancer cells and normal mouse colon epithelium.
Zhou
Jie
J
Center for Pharmacogenetics, Deaprtment of Pharmaceuticals Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
Liu
Mingjie
M
Zhai
Yonggong
Y
Xie
Wen
W
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D015153:Blotting, Western; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology; D003840:Deoxycholic Acid / Q000494:pharmacology; D004127:Dimethylhydrazines / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005434:Flow Cytometry; D045325:HCT116 Cells; D006801:Humans; D020287:In Situ Nick-End Labeling; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D000077297:Pregnane X Receptor; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012293:Rifampin / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C414431:BAG3 protein, human; C494772:BAK1 protein, human; D004127:Dimethylhydrazines; D051034:Inhibitor of Apoptosis Proteins; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D000077297:Pregnane X Receptor; D019253:Proto-Oncogene Proteins c-bcl-2; D011987:Receptors, Steroid; D050998:bcl-2 Homologous Antagonist-Killer Protein; D003840:Deoxycholic Acid; D004317:Doxorubicin; C494833:BIRC2 protein, human; D044767:Ubiquitin-Protein Ligases; D012293:Rifampin