This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chen, Y. Articles by Nie, D. Search for Related Content PubMed PubMed Citation Articles by Chen, Y. Articles by Nie, D.

Human Pregnane X Receptor and Resistance to Chemotherapy in Prostate Cancer

¹ Department of Medical Microbiology, Immunology and Cell Biology, Southern Illinois University, School of Medicine and SimmonsCooper Cancer Institute, Springfield, Illinois and ² Department of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China

Requests for reprints: Daotai Nie, Department of Medical Microbiology, Immunology and Cell Biology, Southern Illinois University School of Medicine and SimmonsCooper Cancer Institute, Springfield, IL 62794-9626. Phone: 217-545-9702; Fax: 217-545-3227; E-mail: dnie{at}siumed.edu.

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. [Cancer Res 2007;67(21):10361–7]

This article has been cited by other articles:

				K. Lichti-Kaiser, D. Brobst, C. Xu, and J. L. Staudinger A Systematic Analysis of Predicted Phosphorylation Sites within the Human Pregnane X Receptor Protein J. Pharmacol. Exp. Ther., October 1, 2009; 331(1): 65 - 76. [Abstract] [Full Text] [PDF]

				S. R. Pondugula, C. Brimer-Cline, J. Wu, E. G. Schuetz, R. K. Tyagi, and T. Chen A Phosphomimetic Mutation at Threonine-57 Abolishes Transactivation Activity and Alters Nuclear Localization Pattern of Human Pregnane X Receptor Drug Metab. Dispos., April 1, 2009; 37(4): 719 - 730. [Abstract] [Full Text] [PDF]

				A. M. Naar and J. K. Thakur Nuclear receptor-like transcription factors in fungi Genes & Dev., February 15, 2009; 23(4): 419 - 432. [Abstract] [Full Text] [PDF]

				W. Lin, J. Wu, H. Dong, D. Bouck, F.-Y. Zeng, and T. Chen Cyclin-dependent Kinase 2 Negatively Regulates Human Pregnane X Receptor-mediated CYP3A4 Gene Expression in HepG2 Liver Carcinoma Cells J. Biol. Chem., November 7, 2008; 283(45): 30650 - 30657. [Abstract] [Full Text] [PDF]

				S. Ekins, V. Kholodovych, N. Ai, M. Sinz, J. Gal, L. Gera, W. J. Welsh, K. Bachmann, and S. Mani Computational Discovery of Novel Low Micromolar Human Pregnane X Receptor Antagonists Mol. Pharmacol., September 1, 2008; 74(3): 662 - 672. [Abstract] [Full Text] [PDF]