The androgen receptor (AR) plays a critical role in growth and progression of prostate cancer. The AR mediates the response to androgens (hormones) such as dihydrotestosterone. Prostate cancer is initially responsive to therapies that inhibit AR signaling, but the disease eventually progresses to an androgen-independent or refractory/advanced state. Understanding and modulating AR function is likely to be an effective way to develop new treatment modalities. Dietary dibenzoylmethane (DBM), a �-diketone derived from natural sources and a constituent of sunscreen has been reported to inhibit growth of mammary, lymphomas, leukemias, skin tumors in rodents and human prostate cancer cells. My laboratory was the first to show that DBM inhibits the proliferation of prostate cancer cells in vitro  in conjunction with an accumulation of cells in the G1 phase of the cell cycle and suppression of AR protein expression.  There is evidence to suggest that progression of prostate cancer to metastatic or advanced disease may occur by alterations in interactions between the AR and its coactivators. Preliminary confocal studies looking at the co-localization of AR and its partners in the presence of DBM (+/- androgen) revealed changes in AR translocation to the nucleus. We have hypothesized that this mechanism occurs through a non-competitive antagonism, likely via allosteric effects on AR and/or its coactivation partners. Since the underlying mechanism of DBM for chemopreventive activity in carcinogenesis remains unknown, a quantitative framework approach is being used to develop a better understanding of the AR signaling complex and its interaction with DBM.

Computational modeling of novel androgen-receptor binding sites in advanced prostate cancer

248th National Meeting (2014)

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