EGCG Has Anti-prostate Cancer Activity by Inhibiting hsp90

描述（由申请人提供）：许多研究已经表明绿色茶在人类和实验动物中的抗癌活性的有效性，并且绿色茶提取物已经达到临床试验以检查其抗癌治疗的功效。表没食子儿茶素-3-没食子酸酯（EGCG），绿色茶中的主要儿茶素，已被证明是引发这种生物活性的主要成分。几项动物研究表明，EGCG可以预防各种癌症，包括自发性和化学诱导的癌症。我们发现EGCG是一种分子伴侣90 kDa热休克蛋白（hsp 90）的抑制剂。我们的总体假设是，报道的EGCG的抗癌活性是由于，至少部分是由于其调节HSP 90功能的能力。这一假设将使用小鼠中人类前列腺癌的独特模型进行测试。据我们所知，这是唯一的这样的模型经历人类上皮恶性转化和转移使用激素混合通常发现在男人，因此代表了所有阶段的人类致癌。使用该模型的体内和体外方法，我们将确定当这些上皮细胞从非致瘤性进展到转化到转移阶段时，是否会观察到对EGCG的差异敏感性。使用最敏感的阶段，我们将进一步确定在浓度和时间依赖性的方式是否EGCG调节hsp 90客户端蛋白的水平和/或功能，一致的概念，EGCG抑制前列腺癌细胞的生长，通过其抑制hsp 90活性的能力。为了进一步区分热休克蛋白90依赖性效应和可能的非热休克蛋白90效应，我们将使用一种创新的蛋白质组学方法来评估EGCG影响各种信号通路的能力。 公共卫生相关性：所提出的研究与人类高度相关，因为1）它们集中于具有真实的和相关的人类兴趣的饮食组分，2）EGCG已被证明是具有未知机制的有效抗癌剂，3）EGCG的抗前列腺癌作用是动物模型和人类中最一致的发现之一，4）前列腺癌估计是美国最常诊断的癌症，5）这些研究将测试关于EGCG作用的特别新颖的假设，6）这些研究将增加我们对hsp 90调节的信号通路及其与前列腺癌关系的理解，7）这些研究将测试EGCG在人类前列腺癌的独特和相关模型中的作用，8）它们将为癌症治疗的新的和新颖的治疗方法提供途径。

DESCRIPTION (provided by applicant): Numerous studies have indicated the effectiveness of green tea for anti-cancer activity in both humans and experimental animals, and green tea extract has reached clinical trials for examination of its efficacy for anti- cancer therapy. Epigallocatechin-3-gallate (EGCG), the major catechin in green tea has been shown to be a primary component eliciting this biological activity. Several animal studies have shown EGCG to protect against a variety of cancers, both spontaneous and chemically induced. We made the novel discovery that EGCG is an inhibitor of the chaperone 90 kDa heat shock protein (hsp90). Our overall hypothesis is that the reported anti-cancer activity of EGCG is due, at least in part, to its ability to modulate hsp90 function. This hypothesis will be tested using a unique model of human prostate cancer in mice. As far as we are aware, this is the only such model undergoing human epithelial malignant transformation and metastasis using a hormone mix normally found in men, thus representing all stages of human carcinogenesis. Using in vivo and in vitro approaches with this model, we will determine whether differential sensitivity to EGCG will be observed as these epithelial cells progress from being non-tumorigenic, to transformed, to metastatic stages. Using the most sensitive stage, we will further determine in a concentration- and time-dependent manner whether EGCG modulates the levels and/or function of hsp90 client proteins, consistent with the notion that EGCG inhibits growth of prostate cancer cells through its ability to inhibit hsp90 activity. To further differentiate between hsp90-dependent effects and possible non-hsp90 effects, we will use an innovative proteomic approach that assess the ability of EGCG to affect a variety of signaling pathways. PUBLIC HEALTH RELEVANCE: The proposed studies are highly relevant for humans in that 1) they focus on dietary components that are of real and relevant human interest, 2) EGCG has been demonstrated to be an effective anti-cancer agent with an unknown mechanism, 3) the anti-prostate cancer effect of EGCG is one of the most consistent findings in both animal models and humand, 4) prostate cancer is estimated to be the most frequently diagnosed cancer in the United States, 5) the studies will test a particularly novel hypothesis for the actions of EGCG, 6) the studies will add to our understanding of the signaling pathways regulated by hsp90 and their relationship to prostate cancer, 7) the studies will test the actions of EGCG in a unique and relevant model of human prostate cancer, and 8) they will offer avenues for new and novel therapeutic approaches for cancer treatment.