Caloric restriction enhances the activity of anti-androgen therapy by inhibiting androgen receptor translation in prostate cancer

Epidemiological studies suggest that diet can impact the incidence, progression, and response to treatment of multiple cancers, including prostate cancer (PCa). In this study, we investigated the use of dietary interventions, specifically caloric or protein restriction, in combination with anti-androgen therapy as a treatment for PCa. We found that caloric restriction through alternate-day fasting (ADF) reduces androgen receptor (AR) expression and signaling. This reduction in AR enhances the antitumor activity of the AR antagonist enzalutamide in multiple mouse models of PCa. Mechanistic studies reveal that nutrient starvation via ADF predominantly decreases AR mRNA translation at the elongation stage due to amino acid limitation. Pharmacological agents that similarly impair translation elongation and promote ribosome collisions mimic the AR translation reduction observed with ADF. We propose that amino acid limitation through ADF impairs translation elongation in PCa, and AR mRNA translation is susceptible to this process, leading to a reduction in AR protein levels and enhancing AR-targeted therapy. This study suggests that fasting-induced caloric restriction may improve the efficacy of anti-androgen therapy in PCa. To investigate transcriptomic changes in B6MyC-CaP tumors in response to alternate-day fasting (ADF) and enzalutamide treatment. B6MyC-CaP cells were implanted subcutaneously into male C57BL/6 mice. Once tumors were established, mice were randomized into four treatment groups: vehicle, enzalutamide (ENZ), alternate-day fasting (ADF), or a combination of ADF and ENZ treatment. Total RNA was isolated from tumors and submitted for RNAseq.