Cancer prevention by use of natural agents against defined molecular targets is a desirable goal. Epidemiological studies and observational data support the notion that high intake of fruits and vegetables may be associated with reduced cancer risk. These studies are consistent with the observations that Asian men who consume low fat, high-fiber plant-based diet rich in flavonoids have lowest prostate cancer incidence in the World. Studies conducted in cell culture have demonstrated that apigenin, a common dietary flavonoid present in fruits and vegetables, afford protection against prostate cancer. Recent studies conducted in our laboratory on pre-clinical model of prostate cancer supports this observation that apigenin possesses both cancer preventive- and therapeutic- properties. Much of the cancer preventive effects of apigenin are attributed due to modulations in signal transduction pathways related to inflammation, proliferation, and apoptosis. Members of the Rel/NF-kappaB family control important network of genes that regulate cell growth, proliferation, inflammation, apoptosis, and adaptive responses against cellular redox balance. Aberrant NFkappaB activation has been implicated in the pathogenesis of many cancer types. Data from our preliminary studies have shown that NF-kappaB/p65 is constitutively activated in human prostate adenocarcinoma and suggest that this transcription factor could be a promising molecular target for the development of preventive and/or therapeutic strategies against this disease. The present proposal capitalizes on these recent novel findings. The central hypothesis to be tested in this proposal is that apigenin will impart cancer preventive- as well as therapeutic- effects against prostate cancer by inhibiting NF-kappaB activation in human prostate carcinoma cells. We will further investigate the relevance of in vitro findings to in vivo situations. Under the proposed specific aims 1-4, we will investigate the molecular mechanisms that can lead to inhibition of NF-kappaB activation by apigenin in i) cell culture system, ii) athymic nude mice xenograft, and iii) transgenic mouse, TRAMP. Specifically, we will investigate how apigenin can mediate these effects through down regulation of NF-kappaB 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 over-expression and suppression techniques to delineate whether the effects of apigenin are directly mediated by the down regulation of NF-kappaB. These results will be compared to those obtained from normal prostate epithelial cells, and the results of this study will elucidate the molecular mechanisms by which apigenin exerts its biological activity on prostate epithelial cells. The outcome of this proposal will define NF-kappaB as an important molecular target and apigenin as promising agent against prostate cancer.
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