AR-dependent phosphorylation and phospho-proteome targets in prostate cancer.

Prostate cancer (CaP) is the second leading cause of cancer-related deaths in Western men. Because androgens drive CaP by activating the androgen receptor (AR), blocking AR's ligand activation, known as androgen deprivation therapy (ADT), is the default treatment for metastatic CaP. Despite an initial remission, CaP eventually develops resistance to ADT and progresses to castration-recurrent CaP (CRPC). CRPC continues to rely on aberrantly activated AR that is no longer inhibited effectively by available therapeutics. Interference with signaling pathways downstream of activated AR that mediate aggressive CRPC behavior may lead to alternative CaP treatments. Developing such therapeutic strategies requires a thorough mechanistic understanding of the most clinically relevant and druggable AR-dependent signaling events. Recent proteomics analyses of CRPC clinical specimens indicate a shift in the phosphoproteome during CaP progression. Kinases and phosphatases represent druggable entities, for which clinically tested inhibitors are available, some of which are incorporated already in treatment plans for other human malignancies. Here, we reviewed the AR-associated transcriptome and translational regulon, and AR interactome involved in CaP phosphorylation events. Novel and for the most part mutually exclusive AR-dependent transcriptional and post-transcriptional control over kinase and phosphatase expression was found, with yet other phospho-regulators interacting with AR. The multiple mechanisms by which AR can shape and fine-tune the CaP phosphoproteome were reflected in diverse aspects of CaP biology such as cell cycle progression and cell migration. Furthermore, we examined the potential, limitations and challenges of interfering with AR-mediated phosphorylation events as alternative strategy to block AR function during CaP progression.