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

Abstract Epidemiologic studies suggest that diet can affect the incidence, progression, and response to treatment in multiple cancers, including prostate cancer. In this study, we investigated the use of dietary interventions, specifically caloric or protein restriction, in combination with antiandrogen therapy as a treatment for prostate cancer. Caloric restriction through alternate-day fasting (ADF) reduced androgen receptor (AR) expression and signaling. This reduction in AR enhanced the antitumor activity of the AR antagonist enzalutamide in multiple mouse models of prostate cancer. Mechanistic studies revealed that nutrient starvation via ADF predominantly decreased AR mRNA translation at the elongation stage due to AA limitation. Pharmacologic agents that similarly impair translation elongation and promote ribosome collisions mimicked the AR translation reduction observed with ADF. Overall, these findings suggest that AA limitation through ADF impairs translation elongation in prostate cancer, to which AR mRNA translation is susceptible, leading to a reduction in AR protein levels and enhancing AR-targeted therapy. Significance: Fasting-induced caloric restriction reduces androgen receptor translation and enhances the activity of enzalutamide, suggesting that dietary intervention could be an effective strategy to enhance prostate cancer sensitivity to antiandrogen therapy. See related commentary by Anzules et al., p. 4045