EGCG Has Anti-prostate Cancer Activity by Inhibiting hsp90

EGCG 通过抑制 hsp90 具有抗前列腺癌活性

基本信息

批准号：
8189491
负责人：
Thomas A Gasiewicz
金额：
$ 22.79万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-15 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8189491
关键词：
Address Affect Aging Animal Model Animals Antineoplastic Agents Biochemical Biological Biological Markers Biological Models Cancer Model Catechin Cells Client Clinical Trials Data Dietary Component Dose Effectiveness Epidemiologic Studies Epigallocatechin Gallate Epithelial Epithelial Cells Green tea Growth Heat shock proteins Hormones Human In Vitro Injury Laboratory Study Malignant - descriptor Malignant Neoplasms Malignant neoplasm of prostate Metastatic to Modeling Molecular Molecular Chaperones Mus Neoplasm Metastasis Pathway interactions Physiological Prevention Prostate Proteins Proteomics Reading Regimen Relative (related person)Reporting Research Research Personnel Signal Pathway Skin Staging Steroids System Testing Therapeutic Time Tissues UV induced United States Universities cancer cell cancer diagnosis cancer therapy carcinogenesis design gallocatechol in vivo inhibitor/antagonist innovation interest killings men mouse model novel novel therapeutic intervention oxidative DNA damage tumor progression tumorigenesis tumorigenic

项目摘要

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.

描述（由申请人提供）：大量研究表明，绿茶对人类和实验动物的抗癌活性有效，绿茶提取物已达到临床试验，以检查其抗癌治疗的功效。 Epigallocatechin-3-Gallate（EGCG），绿茶中的主要儿茶素已被证明是引起这种生物学活性的主要成分。几项动物研究表明，EGCG可以预防自发和化学诱导的各种癌症。我们做出了新的发现，即EGCG是伴侣90 kDa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归因于其调节HSP90功能的能力。该假设将使用小鼠中人类前列腺癌的独特模型进行检验。据我们所知，这是使用通常在男性中发现的激素混合物进行人类上皮性恶性转化和转移的唯一模型，因此代表了人类癌变的所有阶段。使用该模型的体内和体外方法，我们将确定是否会观察到对EGCG的差异敏感性，因为这些上皮细胞从非肿瘤元素发展到转化，到转移阶段。使用最敏感的阶段，我们将以浓度和时间依赖性的方式进一步确定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的生长的观念一致。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。公共卫生相关性：拟议的研究与人类高度相关，因为1）他们专注于具有真实且相关的人类兴趣的饮食成分，2）EGCG已被证明是具有未知机制的有效抗癌剂，3）EGCG的抗攻击性癌症在EGCG的抗癌症中是最一致的，对大多数动物模型均具有癌症，而癌症是癌症的4）。国家，5）研究将对EGCG的作用进行一个特别新颖的假设，6）研究将增加我们对HSP90调节的信号通路及其与前列腺癌的关系的理解，7）这些研究将测试EGCG在独特且相关的人类前列腺癌模型中的EGCG的作用。