MODULATION OF PROTEIN KINASE ACTIVITY BY GENISTEIN IN PROSTATE CANCER

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"DISCONTINUED Genistein is an isoflavinoid which is found in high amounts in soy. Its consumption has been associated with a low incidence of prostate cancer (PCa). We have previously demonstrated that genistein increases PCa cell adhesion at concentrations which are attained in the serum with dietary consumption (i.e. nM levels). If acting in vivo, such a mechanism would serve to block the first step in the metastatic cascade, which involves a decrease in cell adhesion; such a mechanism is also consistent with current epidemiologic studies demonstrating a similar incidence of organ confined prostate cancer in both Eastern and Western countries, and a decreased incidence of metastatic cancer in soy consuming Eastern countries. We previously demonstrated that cell adhesion is associated with translocation of focal adhesion kinase (FAK; a tyrosine kinase) to focal adhesion plaques (areas of cell attachment to extracellular matrix). Once there, FAK forms a complex with /-1-integrin, the major cell adhesion molecule for PCa cells. Recent studies have shown that FAK-/-1-integrin complex formation is an early event, preceding cell adhesion, and is not dependent upon ligand binding to /-1-integrin, nor dependent upon an intact cytoskeleton. Signal transduction through /-1-integrin and FAK is, however, is dependent upon the development of tensile forces, such as are generated during cell adhesion, spreading, or motility. These findings provide important information on the molecular events involved in controlling cell adhesion in PCa. Further investigations have shown that genistein, a ""broad spectrum"" inhibitor of tyrosine kinase activity in vitro, has limited and specific effects upon kinase activity in vivo. While unable to inhibit FAK kinase activity in vitro, genistein specifically decreases in vivo FAK kinase activity. This is important in that increased expression of FAK is associated with PCa cell progression. Our studies went on to demonstrate that FAK inhibition by genistein was associated with the induction of apoptosis. Having shown that genistein may be acting to prevent clinical metastatic prostate cancer by increasing cell adhesion, its efficacy in humans is going to be tested in a series of clinical trials. Two phase I trials will be conducted: one at the University of North Carolina, and one here at the Clinical Center (Raymond Bergan as Principal Investigator)."