Epidemiological studies have shown that higher risk for prostate cancer is perhaps due to environmental (especially diet) rather than genetic differences. There is an association between decreased prostate cancer risk and increased soy consumption (Herbert JR, et al. JNCI 90: 1637-1647, 1998). The soy isoflavone, genistein is believed to be the primary anti-cancer agent found in whole grain cereal food, seeds and soybean products, which may play an important role in the prevention and/or treatment of human prostate cancer. In preliminary studies, we found that genistein inhibits the growth of prostate cancer cell lines with concomitant G2/M cell cycle arrest, up- regulation of p21WAF1 and down-regulation of Cyclin-B and Bcl-2, which may be responsible for the induction of apoptosis observed in genistein treated cells. Furthermore, we also observed down regulation of NF-kappaB function in both androgen responsive as well as androgen non-responsive cell lines. The down regulation in NF-kappaB was found to be concomitant with the down regulation of androgen receptor (AR) and prostate specific antigen (PSA) gene transcription in androgen responsive cells. The down regulation of AR and PSA, and the observed inhibition of cell growth and induction of apoptosis may be mediated by the inactivation of the NF-kappaB pathway. We hypothesize that genistein induces cell growth inhibition and apoptosis by inhibiting NF-kappaB and G2/M cell cycle progression. We also hypothesize that genistein abrogates NF-kappaB function resulting in the down regulation of AR and induction of apoptosis in androgen responsive cells. In this proposal, we will investigate cell growth and apoptotic processes in genistein treated prostate cancer cells by analyzing parameters of cell growth and apoptosis (p21, p53, cyclin B, CDK 1, and Bcl-2/Bax family members) using Northern and Western blot analysis. We will also investigate how genistein can mediate these effects through down regulation of NF-kappaB, AR and PSA by analyzing levels and activity of key kinase molecules and associated mechanisms that are involved in the NF-kappaB signaling pathway. Moreover, we will employ gene transfection studies as well as transfection of AR and PSA reporter constructs to delineate whether the effects of genistein is directly mediated by the down regulation of NF-kappaB, AR and PSA. These results will be compared to those obtained from normal prostate epithelial cells, and the results of this study will elucidate the molecular mechanism(s) by which genistein exerts its biological effects on prostate epithelial cells. In addition, we also propose to test the anti-tumor activity of genistein in prostate cancer animal models and investigate whether the molecular alterations in animal tumors are similar to those observed in vitro.
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