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膳食异黄酮与MDM2致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。染料木黄酮是一种膳食异黄酮，已知在几种人类癌症模型中具有化学预防作用，包括乳腺癌和前列腺癌。然而，其预防癌症和抑制生长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依赖性和非依赖性的致瘤活性。它也被认为是癌症预防和治疗的新靶点。这一建议是基于我们的初步数据，这些数据支持以前未被认识到的染料木素的作用机制：直接下调MDM2致癌基因。我们已经证明，染料木素以剂量依赖的方式抑制人类癌细胞（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，并且与基因素的抗肿瘤作用有关。本研究旨在验证一种中心假设，即抑制MDM2是染料木素发挥其抗癌作用的主要机制。提出了三个假设驱动的特定目标：1)确定染料木素特异性抑制MDM2，这种抑制是化合物发挥其抗癌作用的主要机制；2)评价染料木素在体内对MDM2的防癌作用；3)确定染料木素调控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提供基础，并将为染料木素（可能还有其他膳食异黄酮）为基础的癌症控制方法的作用机制提供知识。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.