Molecular mechanisms of growth inhibition in prostate cancer cells by genistein

Prostate cancer is the most common invasive malignancy and the second leading cause of cancer related deaths in males in the United States. African American males have the highest prostate cancer incidence and mortality rates worldwide, while the incidence is much lower in Vegetarians and men from China and Japan. Epidemiological studies suggest that high intake of dietary isoflavones decreases the risk for the development of clinically detectable prostate cancer. Isoflavones have been proposed as cancer protective compounds in populations with low incidence of prostate disease. Soy contains the isoflavone, genistein, which has been shown to inhibit cell growth of prostate cancer cells in vitro and in vivo. The exact mechanism of its anti-carcinogenic effects are not known, however, there is evidence to suggest that genistein targets specific cell signaling pathways. The purpose of this dissertation proposal was to identify the molecular mechanisms involved in genistein-induced cell growth inhibition in prostate cancer cells. We have established that genistein inhibits prostate cancer cell growth in both androgen-dependent and androgen-independent prostate cancer cells. We have also demonstrated that genistein induces a G2/M cell cycle arrest and modulates several cell cycle regulatory molecules including cyclin B and the growth inhibitory protein, p21WAF1 in prostate cancer cells. In addition to its anti-proliferative effects, genistein induces apoptosis and inhibits the activation of the nuclear transcription factor NF-κB. We have also demonstrated that genistein targets androgen mediated signaling pathways and decreases expression of the androgen receptor and the androgen responsive gene, prostate specific antigen. These studies suggest that cell signaling and regulators of cell cycle and apoptosis are potential targets for prostate cancer prevention by soy isoflavones. Additionally, we have demonstrated that soy isoflavone supplementation decreases NF-κB activation in human lymphocytes and reduces rising PSA levels in prostate cancer patients, suggesting that soy isoflavone supplementation has potential benefits in humans. The results of both the in vitro and in vivo studies strongly support the role of genistein as a chemopreventive and/or therapeutic agent for prostate cancer.