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A natural molecule, urolithin A, downregulates androgen receptor activation and suppresses growth of prostate cancer
Author(s) -
Dahiya Nisha R.,
Chandrasekaran Balaji,
Kolluru Venkatesh,
Ankem Murali,
Damodaran Chendil,
Vadhanam Manicka V.
Publication year - 2018
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.22848
Subject(s) - androgen receptor , downregulation and upregulation , prostate cancer , enzalutamide , cancer research , biology , androgen , cell growth , receptor , medicine , endocrinology , cancer , biochemistry , hormone , genetics , gene
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.