Caloric Restriction Enhances the Efficacy of Anti-Androgen Therapy in Prostate Cancer by Inhibiting Androgen Receptor Translation

Epidemiological studies suggest that diet can impact the incidence, progression, and response to treatment in 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. Caloric restriction through alternate-day fasting (ADF) reduced Androgen Receptor (AR) expression and signaling. This reduction in AR enhanced the anti-tumor activity of the AR antagonist enzalutamide in multiple mouse models of PCa. Mechanistic studies revealed that nutrient starvation via ADF predominantly decreased AR mRNA translation at the elongation stage due to amino acid limitation. Pharmacological agents that similarly impair translation elongation and promote ribosome collisions mimicked the AR translation reduction observed with ADF. Overall, these findings suggest that amino acid limitation through ADF impairs translation elongation in PCa, to which AR mRNA translation is susceptible, leading to a reduction in AR protein levels and enhancing AR-targeted therapy.