Molecular aspects of androgenic signaling and possible targets for therapeutic intervention in prostate cancer.

The androgen axis is of crucial importance in the development of novel therapeutic approaches for non-organ-confined prostate cancer. Recent studies revealed that tumor cells have the ability to synthesize androgenic hormones in an intracrine manner. This recognition opened the way for the development of a novel drug, abiraterone acetate, which shows benefits in clinical trials. A novel anti-androgen enzalutamide that inhibits androgen receptor (AR) nuclear translocation has also been developed and tested in the clinic. AR coactivators exert specific cellular regulatory functions, however it is difficult to improve the treatment because of a large number of coregulators overexpressed in prostate cancer. AR itself is a target of several miRNAs which may cause its increased degradation, inhibition of proliferation, and increased apoptosis. Truncated AR occur in prostate cancer as a consequence of alternative splicing. They exhibit ligand-independent transcriptional activity. Although there has been an improvement of endocrine therapy in prostate cancer, increased intracrine ligand synthesis and appearance of variant receptors may facilitate the development of resistance.