Glucocorticoids can promote androgen-independent growth of prostate cancer cells through a mutated androgen receptor

Abstract

The androgen receptor (AR) is involved in the development, growth and progression of prostate cancer (CaP). CaP often progresses from an androgen-dependent to an androgen-independent tumor, making androgen ablation therapy ineffective. However, the mechanisms for the development of androgen-independent CaP are unclear. More than 80% of clinically androgen-independent prostate tumors show high levels of AR expression. In some CaPs, AR levels are increased because of gene amplification and/or overexpression, whereas in others, the AR is mutated. Nonetheless, the involvement of the AR in the transition of CaP to androgen-independent growth and the subsequent failure of endocrine therapy are not fully understood. Here we show that in CaP cells from a patient who failed androgen ablation therapy, a doubly mutated AR functioned as a high-affinity cortisol/cortisone receptor (ARccr). Cortisol, the main circulating glucocorticoid, and its metabolite, cortisone, both equally stimulate the growth of these CaP cells and increase the secretion of prostate-specific antigen in the absence of androgens. The physiological concentrations of free cortisol and total cortisone in men greatly exceed the binding affinity of the ARccr and would activate the receptor, promoting CaP cell proliferation. Our data demonstrate a previously unknown mechanism for the androgen-independent growth of advanced CaP. Understanding this mechanism and recognizing the presence of glucocorticoid-responsive AR mutants are important for the development of new forms of therapy for the treatment of this subset of CaP.

Androgen receptor and prostate cancer

“…53 Often they make the AR more promiscuous for steroid ligands such that they bind estrogen, aldosterone, cortisone, androgen and the antiandrogen hydroxyflutamide. 54 Significantly, AR mutation can directly promote CaP cell growth and suppress the protective role of p53 pointing to tight regulatory loop between AR and p53. 55,56 Ultimately all recurrent disease progresses to a phase in which it is androgen depletion independent.…”

Inhibition of the SH3 domain-mediated binding of Src to the androgen receptor and its effect on tumor growth

“…AR and ER expression is maintained even in hormone-independent cancers, although their role under these conditions is still poorly understood. More than 80% of clinically androgen independent human prostate tumors show high levels of AR (Zhao et al, 2000). There appear to be different possible mechanisms for acquiring androgen-independence in the presence of AR expression.…”

“…Also, growth factors, such as epidermal growth factor (EGF), could bypass the hormone requirement by directly activating the AR (Culig et al, 1994, Migliaccio et al, 2005. Alternatively, non-androgenic steroids could promote androgen-independent growth of prostate cancer cells through a mutated AR (Zhao et al, 2000). Estrogen independence in the presence of ER might arise via other mechanisms including the ligandindependent ER activation, expression of ER variants, and increased expression of co-activators (Gururaj et al, 2006).…”

Chimeric PSA enhancers exhibit augmented activity in prostate cancer gene therapy vectors

“…Recent clinical and laboratory investigations point to AR-mediated signaling in advanced AI disease even under androgen-depleted conditions. [43][44][45][46] We will be evaluating the activity of our vectors thoroughly in AI models. The precise magnitude of therapeutic gene product needed to mediate effective tumor eradication could be very different, depending upon the therapeutic strategy.…”