EGCG Has Anti-prostate Cancer Activity by Inhibiting hsp90

描述（由申请人提供）：大量研究表明绿茶在人类和实验动物中具有抗癌活性，绿茶提取物已进入临床试验，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可以预防多种癌症，包括自发和化学诱导的癌症。我们发现EGCG是伴侣蛋白90kda热休克蛋白（hsp90）的抑制剂。我们的总体假设是，EGCG的抗癌活性至少部分是由于其调节hsp90功能的能力。这一假设将在一种独特的人类前列腺癌小鼠模型中得到验证。据我们所知，这是唯一一个使用通常在男性中发现的激素混合物进行人类上皮恶性转化和转移的模型，因此代表了人类癌变的所有阶段。使用体内和体外方法，我们将确定在这些上皮细胞从非致瘤性、转化到转移阶段的过程中，是否会观察到对EGCG的不同敏感性。使用最敏感的阶段，我们将进一步以浓度和时间依赖的方式确定EGCG是否调节hsp90客户蛋白的水平和/或功能，这与EGCG通过其抑制hsp90活性的能力抑制前列腺癌细胞生长的观点一致。为了进一步区分hsp90依赖性效应和可能的非hsp90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。

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.