Human Pregnane X Receptor and Resistance to Chemotherapy in Prostate Cancer

Abstract

Resistance to chemotherapy is a significant barrier to the effective management of prostate cancer. Human pregnane X receptor (hPXR), an orphan nuclear receptor known for its activation by many important clinical drugs, interacts with many cellular signaling pathways during carcinogenesis and is a major transcription factor regulating the expression of drug metabolism enzymes, including transporters. It is unknown whether hPXR is a determinant of drug resistance in prostate cancer. In this study, we first detected the expression of hPXR in both normal and cancerous prostate tissues. Pretreatment with SR12813, a potent and selective agonist of hPXR, led to nuclear translocation of PXR in PC-3 cells and increased expression of cytochrome P450 3A4 (CYP3A4) and multidrug resistance 1 (MDR1). SR12813 pretreatment increased resistance of PC-3 cells to Taxol and vinblastine, as assessed by viability and clonogenic survival. To further study the role of hPXR in prostate cancer drug resistance, hPXR expression was knocked down using PXR-targeting short hairpin RNAs. The activities of hPXR toward the promoter of CYP3A4 in hPXR-ablated clones decreased when compared with that of wild-type PC-3 cells. Their sensitivities to Taxol and vinblastine were enhanced by hPXR ablation. Our data here suggest that hPXR may play an important role in prostate cancer resistance to chemotherapeutics.