Pregnane X Receptor as a Therapeutic Target to Inhibit Androgen Activity

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. (Endocrinology 151: 5721-5729, 2010) P rostate cancer is the most common malignancy diagnosed in American men and the second leading cause of male cancer mortality (1). In the 1940s, Charles Huggins found that metastatic prostate cancer responded to androgen deprivation therapy (ADT) (2), which has since become the mainstay of treatment for locally advanced and metastatic prostate cancer.The ADT strategies in prostate cancer patients include orchiectomy and the use of GnRH (also known as LHRH) agonists or antagonists, steroidal and nonsteroidal antiandrogens, and inhibitors for the 5␣-reductase (3). Orchiectomy is a simple surgical procedure, but it has fallen out of favor given its psychological impact and viable medical alternatives for androgen deprivation (4). GnRH agonist therapy is widely used as a medical and reversible castration. GnRH agonists induce a transient increase in plasma testosterone (T) levels during the first week of treatment, causing a "flare" reaction in prostate cancer patients (5). GnRH antagonists do not cause a T surge, but they could be associated with an enhanced risk of ana-

Cytosolic sulfotransferase 2B1b promotes hepatocyte proliferation gene expression in vivo and in vitro

“…The prominent expression of SULT2B1b in skin and its predilection for cholesterol as a substrate are in keeping with its critical role during keratinocyte differentiation and epidermal development (19,43). Similarly, the expression of SULT2A1 in human steroidogenic organs and androgen-dependent tissue (prostate) would be in keeping with its role in steroid hormone deactivation and participation in the prevention of androgen-dependent prostate cancer development (50).…”

Regulation of CYP3A4 and CYP3A5 expression and modulation of “intracrine” metabolism of androgens in prostate cells by liganded vitamin D receptor

“…It has recently been reported that rifampicin will inhibit androgen activity within LAPC4 prostate cancer cells, leading to the proposal of PXR as a potential therapeutic target in prostate cancer treatment (Zhang et al, 2010). While we observe that PXR is negligibly expressed within the context of both LNCaP and LAPC4 cells with its activating ligands having no effect upon CYP3A expression in either of these model systems (data not shown), our respective studies do highlight the potential for nuclear receptor-mediated pathways to impact upon prostatic intracrine metabolism.…”

Lxrα Regulates the Androgen Response in Prostate Epithelium

“…In these tumors, fas, srebp1c, abca1, and cyp-27 gene expressions decrease during androgen insensitivity evolution. Interestingly, another partner of retinoid X receptor, the pregnane X receptor (NR1I2) has been demonstrated to inhibit androgen-dependent proliferation of LAPC-4 cells (41). This raises the question whether LXR and pregnane X receptor could act through a similar molecular mechanism.…”