The Development And Therapy Of Castration Resistent Prostate Cancer

Prostate cancer (PCa) is the most common malignant tumor in male in American and Europe. In China, because of the changes of living habits, diet and age structure, the PCa incidence rate is increasing year after year. As androgen/androgen receptor (A/AR) play vital roles in PCa cells growth, the androgen deprivation therapy (ADT) has been the main therapeutic approach to treat PCa patients. However, after an average of24months validity, the tumors almost always recur and no longer respond to ADT.AR roles in PCa cells’deaths are dual and complecated, so ADT in PCa may have different effects on different cell death. In this study, we first studied the role of AR in Entosis and found AR could go through Rho/ROCK pathway to ehance Entosis. This study contributes to the AR roles in PCa cells’deaths. So far, there are5cell deaths have been studied in PCa, and according to the roles of AR in cell deaths in PCa, ADT would promote apoptosis, necrosis and autophagy while it would suppress anokis and entosis. Addition to AR roles in cell proliferation, AR roles in cell deaths further explain the dual roles of AR in PCa.Based on the above hypothesis, we further studied the effect of ADT on fatty acid synthetase (FASN) and PCa stem/progenitor cells. We found ADT has littlle effect on FASN expression and FASN-induced cell growth in castration condition. That is at least one of the reason why ADT fails in castration resistant prostate cancer (CRPC). What’s more, we found ADT wound increase PCa stem/progenitor cells, which were more malignant and their invasion capability was stronger.In the opposite and good way, ASC-J9, a newly developed anti-PCa drug, could suppress FASN through both AR (ASC-J9-AR-SREBP1-FASN) pathway and non-AR (ASC-J9-PI3K/AKT-SREBP1-FASN) pathway. So it still have strong effect to suppress PCa in castration resistant stage. What’s more, ASC-J9was able suppress PCa stem/progenitor cell invasion through AKT-EZH2-STAT3pathway. All these advantages make ASC-J9better than current ADT drugs (Casodex and MDV3100). So ASC-J9might be the potential next generation treatment to fight PCa.