Non-canonical androgen signaling pathways and implications in prostate cancer

Androgen signaling is a critical determinant of timely and proper development of all male organs including the prostate. Maturation of prostate and its neoplastic transformation is intricately associated with accurate androgen signaling. Ablation of androgen has therefore been the primary treatment mechanism of Prostate cancer (PCa) patients for several decades. Upon removal, the tumor recedes for a while, yet it reappears soon, in an androgen independent state, untreatable by current therapeutic regimens. Studies reveal that apart from the classical androgen signaling pathway known and targeted for almost a century, there exist several non-canonical pathways, with marked impact on classical androgen signaling and PCa growth. These include non-genomic signaling by androgens via alternate membrane GPCRs, signaling by non-androgens that ultimately impact the androgen signaling pathway, or an integration of non-genomic and genomic response as seen in case of protein kinase A activation. Accurate understanding of these various non-canonical androgen signaling pathways and their influence on the typical androgen signaling pathway can help design important interventions for PCa patients. This review analyses in detail the various non-classical androgen signaling pathways and their impact, if any, on classical mode of androgen action and PCa.