A natural molecule, urolithin A, downregulates androgen receptor activation and suppresses growth of prostate cancer

Androgen ablation therapy is the primary therapeutic option for locally advanced and metastatic castration‐resistant prostate cancer (CRPC). We investigated therapeutic effect of a dietary metabolite Urolithin A (UroA) and dissected the molecular mechanism in CRPC cells. Treatment with UroA inhibited cell proliferation in both androgen receptor‐positive (AR + ) (C4‐2B) and androgen receptor‐negative (AR − ) (PC‐3) cells however, AR + CaP cells were more sensitive to UroA treatment as compared with AR − CaP cells. Inhibition of the AR signaling was responsible for the UroA effect on AR + CaP cells. Ectopic expression of AR in PC‐3 cells sensitized them to UroA treatment as compared to the vector‐expresseing PC‐3 cells, which suggests that AR could be a target of UroA. Similarly, in enzalutamide‐resistant C4‐2B cells, a downregulation of AR expression also suppressed cell proliferation which was observed with the UroA treatment. Oral administration of UroA significantly suppressed the growth of C4‐2B xenografts ( P  = 0.05) compared with PC‐3 xenografts ( P  = 0.069) without causing toxicity to animals. Immunohistochemistry analysis confirmed in vitro findings such as downregulation of AR/pAKT signaling in UroA‐treated C4‐2B tumors, which suggests that UroA may be a potent chemo‐preventive and therapeutic agent for CRPC.