Pregnane X Receptor as a Therapeutic Target to Inhibit Androgen Activity

• 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
• DOI: 10.1210/en.2010-0708
• EISSN: 1945-7170
• ISSN: 0013-7227

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.