The Protein Kinase A (PKA) Intracellular Pathway and Androgen Receptor: A Novel Mechanism Underlying the Castration-resistant and Metastatic Prostate Cancer

Abstract

Androgen deprivation therapy (ADT) in the form of medical or surgical castration has been used as the standard therapy for localized and advanced prostate cancer (PCa). Although ADT leads to the initial regression of tumors, the recurrence of more aggressive PCa, also termed as castration-resistant PCa (CRPC) is inevitable. Androgen receptor (AR) and its associated network have been proposed to play central role in the progression of CRPC. Given that CRPC exhibits the nature of heterogeneity and complexity, multiple cellular pathways may cooperatively promote progression of CRPC and render the tumors insensitive to therapy. In this article, we will review some of the recent findings and clinical interventions to identify the novel targets and alternative signaling pathways associated with AR that may allow the aggressive forms of PCa to recur and become resistance to therapy. We will discuss about the role of the cyclic adenosine monophosphate (cAMP) activated protein kinase A (PKA) pathway in the progression of CRPC. The emerging evidence suggests that several key factors in PKA signalings may play important roles in the recurrence and treatment response of CRPC, and that PKA pathways may serve as potential diagnostic and predictive biomarkers for CRPC. We will also update with the information on the novel therapeutic strategies that have been designed and tested in laboratories to inhibit PCa growth by targeting both AR and PKA pathways. Understanding of the molecular mechanisms underlying the progression of CRPC and treatment resistance will provide novel insight for effective treatment of CRPC.