α-Mangostin Promotes In Vitro and In Vivo Degradation of Androgen Receptor and AR-V7 Splice Variant in Prostate Cancer Cells

SIMPLE SUMMARY: Castration-resistant prostate cancer often develops in response to continued drug treatment and is characterized by mutations in the androgen receptor. Commonly used anti-androgen drugs are ineffective at targeting these cells; interestingly, our study evaluated a compound from Garcinia mangostana that has activity against castration-resistant prostate cancer cells. Our data shows that this compound effectively decreases cell viability and degrades the androgen receptor, regardless of mutations present in the androgen receptor. We suggest that this may be achieved through the activation of a cell stress chaperone protein, BiP, which our compound both binds to and promotes binding with the androgen receptor. Finally, this compound has in vivo anticancer activity and decreases mutant androgen receptor expression in vivo as well. Novel compounds that can degrade mutant androgen receptors present an opportunity to target castration-resistant prostate cancer cells through a unique mechanism. ABSTRACT: A major limitation of current prostate cancer pharmacotherapy approaches is the inability of these compounds to target androgen receptor variants or mutants that develop during prostate cancer progression. The demand for novel therapeutics to prevent, slow, and treat prostate cancer is significant because FDA approved anti-androgens are associated with adverse events and can eventually drive drug-resistant prostate cancer. This study evaluated α-mangostin for its novel ability to degrade the androgen receptor and androgen receptor variants. α-Mangostin is one of more than 70 isoprenylated xanthones isolated from Garcinia mangostana that we have been evaluating for their anticancer potential. Prostate cancer cells treated with α-mangostin exhibited decreased levels of wild-type and mutated androgen receptors. Immunoblot, immunoprecipitation, and transfection experiments demonstrated that the androgen receptor was ubiquitinated and subsequently degraded via the proteasome, which we hypothesize occurs with the assistance of BiP, an ER chaperone protein that we have shown to associate with the androgen receptor. We also evaluated α-mangostin for its antitumor activity and promotion of androgen receptor degradation in vivo. In summary, our study demonstrates that androgen receptor degradation occurs through the novel activation of BiP and suggests a new therapeutic approach for prostate cancer.