EGCG Inhibits AhR and Carcinogenesis by Modulating Hsp90

EGCG 通过调节 Hsp90 抑制 AhR 和致癌作用

• 批准号: 7014379
• 负责人: Thomas A Gasiewicz
• 金额: $ 19.5万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7014379
• 关键词: DNA binding protein; antineoplastics; aromatic hydrocarbon receptor; binding sites; cell free system; cell line; cell transformation; chemical carcinogenesis; dietary supplements; dioxins; flavonoids; heat shock proteins; immunoprecipitation; molecular chaperones; neoplastic growth; nutrition related tag; protein structure function; tea

DESCRIPTION (provided by applicant): The possibility that green tea (GT) and its components protect against certain types of cancer has become an increasing health interest. Studies indicate that GT exerts preventive effects in animal models of chemical carcinogenesis and spontaneously developing tumors. The exact mechanism by which GT and its components act is unknown. Preliminary studies demonstrated that GT extracts and several components are effective at antagonizing transcriptional events mediated by binding of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a potent toxicant and carcinogen, to the aryl hydrocarbon receptor (AhR). It was determined that epigallocatechin-3-gallate (EGCG), a component of GT, blocks AhR-mediated transcription not by binding to the AhR, but through its interaction with the 90 kDa heat shock chaperone protein (hsp90). It is hypothesized that EGCG is a hsp90 inhibitor and this contributes to its reported anti-cancer activity. Using isolated rodent and human cell lines and cell-free model systems, we will determine the exact binding site for EGCG on hsp90 and examine how this binding alters hsp90 conformation and function. Using similar procedures and immunoprecipitation, experiments will be performed to further characterize the AhR protein complex associated with EGCG-bound hsp90 to determine how DNA binding of the AhR is inhibited. Hsp90 regulates the function of a large number of client proteins, many of which are important in the growth and survival of cancer cells. Additional studies will determine if EGCG alters the levels and/or activity of several hsp90 client proteins that may play a role in the malignant transformation or growth of tumor cells.

描述（由申请人提供）：绿茶（GT）及其组成部分可以预防某些类型的癌症的可能性已成为越来越多的健康利益。研究表明，GT在化学癌变动物模型和自发发展肿瘤的动物模型中发挥预防作用。 GT及其组件作用的确切机制尚不清楚。初步研究表明，GT提取物和几个成分在拮抗2,3,7,8-四氯迪本佐-P-二恶英（TCDD）的结合介导的转录事件方面有效，这是一种有效的毒物和致癌物，与芳基水合碳受体（AHR）。据确定，epigallocatechin-3-gallate（EGCG）是GT的一个成分，它通过与AHR结合而是通过与90 kDa热激伴侣蛋白（HSP90）的相互作用来阻止AHR介导的转录。假设EGCG是HSP90抑制剂，这有助于其报告的抗癌活性。使用孤立的啮齿动物和人类细胞系以及无细胞模型系统，我们将确定HSP90上EGCG的精确结合位点，并检查这种结合如何改变HSP90的构象和功能。使用类似的程序和免疫沉淀，将进行实验，以进一步表征与与EGCG结合的HSP90相关的AHR蛋白复合物，以确定如何抑制AHR的DNA结合。 HSP90调节大量客户蛋白的功能，其中许多对癌细胞的生长和存活很重要。其他研究将确定EGCG是否改变了可能在肿瘤细胞的恶性转化或生长中起作用的几种HSP90客户蛋白的水平和/或活性。