Pregnane X receptor as a therapeutic target to inhibit androgen activity

Bin Zhang, Qiuqiong Cheng, Zhimin Ou, Jung Hoon Lee, Meishu Xu, Upasana Kochhar, Songrong Ren, Min Huang, Beth Pflug, Wen Xie

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)5721-5729
Number of pages9
JournalEndocrinology
Volume151
Issue number12
DOIs
StatePublished - Dec 2010

Fingerprint

Androgens
Prostatic Neoplasms
Rifampin
Therapeutics
Small Interfering RNA
pregnane X receptor
Hormones
Testosterone Propionate
Androgen Receptors
Xenobiotics
Enzymes
Cytoplasmic and Nuclear Receptors
Transgenes
Cytochrome P-450 Enzyme System
Prostate
Regeneration
Homeostasis
Down-Regulation
Pharmacology
Injections

ASJC Scopus subject areas

  • Endocrinology

Cite this

Zhang, B., Cheng, Q., Ou, Z., Lee, J. H., Xu, M., Kochhar, U., ... Xie, W. (2010). Pregnane X receptor as a therapeutic target to inhibit androgen activity. Endocrinology, 151(12), 5721-5729. https://doi.org/10.1210/en.2010-0708

Pregnane X receptor as a therapeutic target to inhibit androgen activity. / Zhang, Bin; Cheng, Qiuqiong; Ou, Zhimin; Lee, Jung Hoon; Xu, Meishu; Kochhar, Upasana; Ren, Songrong; Huang, Min; Pflug, Beth; Xie, Wen.

In: Endocrinology, Vol. 151, No. 12, 12.2010, p. 5721-5729.

Research output: Contribution to journalArticle

Zhang, B, Cheng, Q, Ou, Z, Lee, JH, Xu, M, Kochhar, U, Ren, S, Huang, M, Pflug, B & Xie, W 2010, 'Pregnane X receptor as a therapeutic target to inhibit androgen activity', Endocrinology, vol. 151, no. 12, pp. 5721-5729. https://doi.org/10.1210/en.2010-0708
Zhang B, Cheng Q, Ou Z, Lee JH, Xu M, Kochhar U et al. Pregnane X receptor as a therapeutic target to inhibit androgen activity. Endocrinology. 2010 Dec;151(12):5721-5729. https://doi.org/10.1210/en.2010-0708
Zhang, Bin ; Cheng, Qiuqiong ; Ou, Zhimin ; Lee, Jung Hoon ; Xu, Meishu ; Kochhar, Upasana ; Ren, Songrong ; Huang, Min ; Pflug, Beth ; Xie, Wen. / Pregnane X receptor as a therapeutic target to inhibit androgen activity. In: Endocrinology. 2010 ; Vol. 151, No. 12. pp. 5721-5729.
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