With prostate cancer being ranked as the second leading cause of cancer related deaths in US men, itcontinues to pose a great challenge to public health. The androgen receptor (AR) plays an important part inthe development and progression of prostate cancer. The AR mediates the response to androgens(hormones) such as dihydrotestosterone making it a validated drug target in prostate cancer and otherhuman diseases. Prostate cancer is initially responsive to therapies that inhibit AR signaling, but thedisease eventually advances to an androgen-independent state. In order to combat the progression of thisdisease, there is a need to identity new chemotherapeutic agents with novel mechanisms of action. Thelong-term objective of this project is to determine the molecular mechanism of chemoprevention bydibenzoylmethane (DBM). Dibenzoylmethane (DBM) is a minor constituent of licorice that is widely used insunscreens as an ultraviolet blocking agent. In our laboratory, we have shown that DBM inhibits theproliferation of prostate cancer cells in vitro along with an accumulation of cells in the G1 phase of the cellcycle. The mechanistic basis for these antiproliferative effects are unknown. When theandrogen-responsive LNCaP prostate cancer cells were exposed to DBM, we observed a loss in detectionof the AR and an increase in expression of Hsp70 (an AR coactivator) by Western analysis in a dosedependent manner. There is evidence to suggest that progression of prostate cancer to metatasis oradvanced disease may occur by alterations in interactions and expression between the AR and itscoactivators. Western blot data was substantiated by our recent laboratory findings that DBM inducedpronounced changes in the expression of Hsp70 by proteomic analysis. Experiments with positiveoutcomes have been done to test the effectiveness of DBM in the TRAMP mouse model of human prostatecancer and to evaluate its toxicity profile. In this present study, we attempt to advance toward elucidatingthe molecular basis for the antineoplastic effects of DBM in prostatic carcinoma cells by examining ARtransactivation (signaling) through deregulation of AR interaction with its HSP complex.
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