Pregnane X Receptor as a Therapeutic Target to Inhibit Androgen Activity

The androgen-androgen receptor signaling pathway plays an important role in the pathogenesis of prostate cancer. Accordingly, androgen deprivation has been the most effective endocrine therapy for hormone-dependent prostate cancer. Here, we report a novel pregnane X receptor (PXR)-mediated and metab...

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Bibliographic Details
Published in:	Endocrinology (Philadelphia) Vol. 151; no. 12; pp. 5721 - 5729
Main Authors:	Zhang, Bin, Cheng, Qiuqiong, Ou, Zhimin, Lee, Jung Hoon, Xu, Meishu, Kochhar, Upasana, Ren, Songrong, Huang, Min, Pflug, Beth R, Xie, Wen
Format:	Journal Article
Language:	English
Published:	Chevy Chase, MD Endocrine Society 01-12-2010 Oxford University Press The Endocrine Society
Subjects:	Agonists Androgen receptors Androgens Animals Biological and medical sciences Cell Line, Tumor Cell proliferation Cytochrome P-450 Enzyme System - genetics Cytochrome P-450 Enzyme System - metabolism Cytochrome P450 Cytochromes P450 Down-regulation Drug metabolism Endocrine therapy Enzymes Fundamental and applied biological sciences. Psychology Gene Expression Homeostasis Humans Hydroxysteroids Male Mice Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Orchiectomy Pathogenesis Pregnane X receptors Pregnenolone Carbonitrile - pharmacology Prostate - physiology Prostate cancer Prostatic Neoplasms Receptors Receptors, Androgen - metabolism Receptors, Steroid - agonists Receptors, Steroid - antagonists & inhibitors Receptors, Steroid - genetics Receptors, Steroid - metabolism Regeneration Ribonucleic acid Rifampin RNA Signal transduction siRNA Sulfotransferase Sulfotransferases - genetics Sulfotransferases - metabolism Testosterone Testosterone - administration & dosage Testosterone - blood Testosterone - metabolism Testosterone - pharmacology Testosterone propionate Testosterone Propionate - pharmacology Therapeutic targets Transgenes Vertebrates: endocrinology Androgen Sex steroid hormone Pregnane X receptor
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Summary:	The androgen-androgen receptor signaling pathway plays an important role in the pathogenesis of prostate cancer. Accordingly, androgen deprivation has been the most effective endocrine therapy for hormone-dependent prostate cancer. Here, we report a novel pregnane X receptor (PXR)-mediated and metabolism-based mechanism to reduce androgenic tone. PXR is a nuclear receptor previously known as a xenobiotic receptor regulating the expression of drug metabolizing enzymes and transporters. We showed that genetic (using a PXR transgene) or pharmacological (using a PXR agonist) activation of PXR lowered androgenic activity and inhibited androgen-dependent prostate regeneration in castrated male mice that received daily injections of testosterone propionate by inducing the expression of cytochrome P450 (CYP)3As and hydroxysteroid sulfotransferase (SULT)2A1, which are enzymes important for the metabolic deactivation of androgens. In human prostate cancer cells, treatment with the PXR agonist rifampicin (RIF) inhibited androgen-dependent proliferation of LAPC-4 cells but had little effect on the growth of the androgen-independent isogenic LA99 cells. Down-regulation of PXR or SULT2A1 in LAPC-4 cells by short hairpin RNA or small interfering RNA abolished the RIF effect, indicating that the inhibitory effect of RIF on androgens was PXR and SULT2A1 dependent. In summary, we have uncovered a novel function of PXR in androgen homeostasis. PXR may represent a novel therapeutic target to lower androgen activity and may aid in the treatment and prevention of hormone-dependent prostate cancer. This study uncovers a novel mechanism of PXR-mediated and metabolism-based androgen deprivation, which may aid in the treatment and prevention of prostate cancer.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Address all correspondence and requests for reprints to: Dr. Wen Xie, Center for Pharmacogenetics, University of Pittsburgh, Pittsburgh, Pennsylvania 15261. E-mail: wex6@pitt.edu.
ISSN:	0013-7227 1945-7170
DOI:	10.1210/en.2010-0708