EGCG Has Anti-prostate Cancer Activity by Inhibiting hsp90

EGCG 通过抑制 hsp90 具有抗前列腺癌活性

• 批准号: 8332788
• 负责人: Thomas A Gasiewicz
• 金额: $ 19.12万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 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/8332788
• 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; Diet; 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

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.

描述(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，绿茶提取物已进入临床试验，以检验其抗癌治疗的有效性。表没食子儿茶素没食子酸酯(EGCG)是绿茶中的主要儿茶素，已被证明是激发这一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，包括自发的和化学诱导的。我们的新发现是，EGCG是90 kDa热休克蛋白(HSP90)的伴侣抑制物。我们的总体假设是，已报道的EGCG的抗癌活性至少部分归因于它调节HSP90功能的能力。这一假设将使用一种独特的人类前列腺癌小鼠模型进行验证。据我们所知，这是唯一一种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，因此代表了人类癌症发生的所有阶段。通过使用体内和体外方法，我们将确定当这些上皮细胞从非致瘤阶段发展到转化阶段，再到转移阶段时，是否会观察到对EGCG的差异敏感性。在最敏感的阶段，我们将以浓度和时间依赖的方式进一步确定EGCG是否调节HSP90客户蛋白的水平和/或功能，这与EGCG通过抑制HSP90活性来抑制前列腺癌细胞生长的概念一致。为了进一步区分HSP90依赖的效应和可能的非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。