Dietary Chemopreventive Components/Oncogene Interaction and Cancer

描述（由申请人提供）：该项目的长期目标是表征饮食异黄酮和 MDM2 癌基因之间的相互作用，评估 MDM2 作为癌症化学预防新靶点的潜力，并将这些发现转化为更合理的人类癌症预防方法。金雀异黄酮是一种膳食异黄酮，已知对多种人类癌症模型（包括乳腺癌和前列腺癌）具有化学预防作用。然而，其癌症预防和生长抑制作用的机制尚不完全清楚。 MDM2癌蛋白在包括前列腺癌和乳腺癌在内的各种类型的人类癌症中具有p53依赖性和独立性的致瘤活性。它也被建议作为癌症预防和治疗的新靶点。该提议基于我们的初步数据，这些数据支持金雀异黄素先前未被认识的作用机制：直接下调 MDM2 癌基因。我们已经证明，金雀异黄素以剂量依赖的方式抑制人癌细胞（和正常细胞）中MDM2的表达，并且抑制作用发生在转录和翻译后水平，并且抑制作用发生在体内，并且与金雀花素的抗肿瘤作用有关。该提案旨在检验以下中心假设：抑制 MDM2 是金雀异黄素发挥抗癌作用的主要机制。提出了三个假设驱动的具体目标：1）。确定金雀花素特异性抑制 MDM2，并且这种抑制是该化合物发挥其抗癌作用的主要机制。 2）。评估金雀异黄素对 MDM2 的体内癌症预防作用；和3）。确定金雀异黄素调节 MDM2 的机制。成功完成具体目标将为进一步研究 MDM2 作为癌症预防和治疗的靶点奠定基础，并将产生有关基于染料木黄酮（可能还有其他膳食异黄酮）的癌症控制方法的作用机制的知识。利用 MDM2 相关途径预防和治疗人类癌症也具有相当大的潜力。

DESCRIPTION (provided by applicant): The long-term objectives of this project are to characterize the interaction between dietary isoflavone and MDM2 oncogene, to evaluate the potential of MDM2 as novel targets for cancer chemoprevention, and to translate these findings into more rational approach to prevention of human cancers. Genistein is a dietary isoflavone known to have chemopreventive effects in several human cancer models, including those of the breasts and prostate. However, the mechanisms for its cancer preventive and growth inhibitory effects are not fully understood. The MDM2 oncoprotein has p53-dependent and -independent tumorigenic activities in various types of human cancers including prostate and breast cancers. It also has been suggested as a novel target for cancer prevention and treatment. This proposal is based on our preliminary data that support a previously unrecognized mechanism of action for genistein: direct down-regulation of the MDM2 oncogene. We have demonstrated that, in a dose-dependent manner, genistein inhibits MDM2 expression in human cancer cells (and normal cells), and that the inhibitory effects occur at both transcriptional and post-translational levels, and that the inhibitory effects occur in vivo and are related to genitein's anti-tumor effects. This proposal is designed to test the central hypothesis that inhibition of MDM2 is the major mechanism by which genistein exerts its anti-cancer effects. Three hypothesis-driven specific aims are proposed: 1). to establish that genistein specifically inhibits MDM2 and that this inhibition is the primary mechanism by which the compound exerts its anti-cancer effects.; 2). to evaluate the in vivo effects of genistein on MDM2 with respect to its cancer preventive effects; and 3). to determine the mechanisms by which genistein regulates MDM2. Successful completion of the specific aims will provide a basis for further investigation of MDM2 as a target for cancer prevention and treatment and will generate knowledge with respect to mechanisms of action for genistein (and maybe other dietary isoflavones)-based cancer control approaches. There also is considerable potential of exploiting MDM2-associated pathways for human cancer prevention and therapy.