Experimental evidence of persistent androgen-receptor-dependency in castration-resistant prostate cancer

Abstract

In the majority of castration-resistant prostate cancer (CRPC), prostate-specific antigen (PSA), product of a gene that is almost exclusively regulated by the androgen receptor (AR), still acts as a serum marker reflecting disease burden, indicating that AR signaling is activated even under castrate level of serum androgen. Accumulated evidence shows that transcriptional ability of AR is activated both in ligand-dependent and -independent manners in CRPC cells. Some androgen-independent sublines derived from originally androgen-dependent LNCaP prostate cancer cells overexpress the AR and PSA, for which silencing the AR gene suppresses cellular proliferation. The overexpression of the AR confers androgen-independent growth ability on androgen-dependent prostate cancer cells. Some patient-derived prostate cancer xenograft lines also acquire castration-resistant growth ability secreting PSA. More recent publications have shown that the AR activated in CRPC cells regulates distinct gene sets from that in androgen-dependent status. This concept provides very important insights in the development of novel anti-prostate cancer drugs such as new generation anti-androgens and CYP17 inhibitors.

Figure 1

Schematic mechanisms for castration-resistant activation of the androgen receptor (AR). (A) De novo androgen synthesis results sustained levels of intratumoral androgens; (B) Genetic, epigenetic, post-transcriptional, or post-translational aberration that increases abundance of AR leads to ligand-independent activation or non-specific ligand recognition; (C) A mutation on the ligand-binding region also causes non-specific ligand recognition; (D) Truncated splice variants lacking the ligand-binding region, post-translational modification such as serine/threonine or tyrosine phosphorylation, or interaction with co-activating factors activates AR in a ligand-independent manner.