Signaling Pathways That Control Apoptosis in Prostate Cancer

SIMPLE SUMMARY: Therapies that inhibit androgen receptor signaling induce cell death by apoptosis in prostate epithelium and involution of non-malignant prostate gland, but are not effective against advanced prostate cancer. Recent evidence suggests that activation of androgen receptors in prostate stroma cells induces secretion of paracrine factors that control apoptosis in prostate epithelium. The nature of these paracrine factors, and of the signaling pathways they activate in prostate epithelial cells as well as the apoptosis regulating molecules targeted by these pathways remains unknown. This review summarizes the information on the proteins that regulate apoptosis in prostate cells, on signaling pathways that regulate these proteins, and provides an overview of clinical trials that target signaling pathways in prostate cancer. Understanding the intercellular communications and apoptosis regulation in normal prostate glands and in prostate tumors is essential for the design of curative personalized therapies for advanced prostate cancer. ABSTRACT: Prostate cancer is the second most common malignancy and the fifth leading cancer-caused death in men worldwide. Therapies that target the androgen receptor axis induce apoptosis in normal prostates and provide temporary relief for advanced disease, yet prostate cancer that acquired androgen independence (so called castration-resistant prostate cancer, CRPC) invariably progresses to lethal disease. There is accumulating evidence that androgen receptor signaling do not regulate apoptosis and proliferation in prostate epithelial cells in a cell-autonomous fashion. Instead, androgen receptor activation in stroma compartments induces expression of unknown paracrine factors that maintain homeostasis of the prostate epithelium. This paradigm calls for new studies to identify paracrine factors and signaling pathways that control the survival of normal epithelial cells and to determine which apoptosis regulatory molecules are targeted by these pathways. This review summarizes the recent progress in understanding the mechanism of apoptosis induced by androgen ablation in prostate epithelial cells with emphasis on the roles of BCL-2 family proteins and “druggable” signaling pathways that control these proteins. A summary of the clinical trials of inhibitors of anti-apoptotic signaling pathways is also provided. Evidently, better knowledge of the apoptosis regulation in prostate epithelial cells is needed to understand mechanisms of androgen-independence and implement life-extending therapies for CRPC.