MODULATION OF PROTEIN KINASE ACTIVITY BY GENISTEIN IN PROSTATE CANCER

“Genistein is an isoflavinoid 在大豆中含量很高。它的消费一直是 与前列腺癌（PCa）的低发病率相关。我们有 先前证明染料木黄酮增加PCa细胞粘附 在血清中达到的浓度下， 消耗（即nM水平）。如果在体内起作用， 将阻断转移级联反应的第一步， 涉及细胞粘附的减少;这种机制也 与当前流行病学研究一致， 器官局限性前列腺癌的发病率在东部和南部地区相似， 和西方国家，并降低了转移性 食用大豆的东方国家的癌症。我们之前 表明细胞粘附与细胞膜的转位有关， 粘着斑激酶（FAK;一种酪氨酸激酶）对粘着斑 斑块（细胞附着于细胞外基质的区域）。一旦 在那里，FAK与β-1-整联蛋白形成复合物， PCa细胞的粘附分子。最近的研究表明 FAK-/-1-整联蛋白复合物的形成是早期事件， 细胞粘附，并且不依赖于配体结合， 1 - 1-整联蛋白，也不依赖于完整的细胞骨架。信号 然而，通过β-l-整联蛋白和FAK的转导是， 取决于张力的发展，例如 在细胞粘附、扩散或运动过程中产生。这些 这些发现提供了有关分子事件的重要信息， 参与控制PCa中的细胞粘附。进一步调查 染料木黄酮，一种“广谱”的 体外酪氨酸激酶活性，具有有限和特定的影响， 体内激酶活性。虽然不能抑制FAK激酶活性， 在体外，染料木黄酮特异性降低体内FAK激酶活性。 这是重要的，因为FAK表达的增加与 前列腺癌细胞进展。我们的研究继续证明， 金雀异黄素对FAK的抑制作用与诱导 凋亡已经证明染料木黄酮可以防止 临床转移性前列腺癌通过增加细胞粘附，其 对人体的疗效将在一系列临床试验中进行测试。 将进行两项第一阶段试验：一项在北方大学进行， 卡罗莱纳和一个在这里的临床中心（雷蒙德伯根作为 首席研究员）。"

"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)."