(-)-Epigallocatechin-3-gallate is a novel Hsp90 inhibitor.
(-)-Epigallocatechin-3-gallate is a novel Hsp90 inhibitor.
复制标题
DOI：
10.1021/bi801637q
复制
发表时间：
2009-01-20
期刊：
影响因子：
2.9
通讯作者：
Gasiewicz TA
中科院分区：
文献类型：
--
作者：
Yin Z;Henry EC;Gasiewicz TA
（-）-表没食子儿茶素-3-没食子酸酯（EGCG）是绿茶的主要成分，可以预防某些类型的癌症，尽管其机制尚未确定。先前有研究表明，EGCG可阻断强致癌物2,3,7,8-四氯二苯并-对二恶英（TCDD）诱导的芳烃受体（AhR）介导的转录。与其他直接结合AhR的AhR拮抗剂不同，EGCG通过结合hsp90抑制AhR介导的转录。我们假设EGCG通过作为hsp90抑制剂发挥抗ahr和抗癌作用。通过蛋白水解足迹、免疫沉淀和ATP-琼脂糖拉下实验，发现EGCG直接调节hsp90的构象，并结合在c端ATP结合位点或附近。通过其介导变性荧光素酶的再折叠的能力来评估Hsp90伴侣的功能，EGCG处理抑制了Hsp90伴侣的功能。在c端发生的Hsp90二聚化也被EGCG处理抑制。共免疫沉淀研究表明，EGCG稳定了包括hsp90和XAP2（乙型肝炎病毒x相关蛋白2）的AhR复合物，并降低了芳基烃核转运子（Arnt）与配体活化的AhR的关联。因此，EGCG通过其与hsp90结合的能力，阻断AhR反应元件（AhRE）的识别。这些研究表明了EGCG抑制配体诱导的AhRE结合和ahr介导的转录活性的新机制。在egcg处理的人卵巢癌SKOV3细胞中，观察到几种与癌症相关的hsp90客户蛋白水平下降，如ErbB2、Raf-1和phospho-AKT。EGCG还改变了hsp90与几种伴侣蛋白的关联。总之，这些数据表明EGCG是一种新的hsp90抑制剂。需要进一步的研究来确定这是否在EGCG的抗肿瘤作用中起作用。
(-)-Epigallocatechin-3-gallate (EGCG), a major component of green tea, protects against certain types of cancers, although the mechanism has not yet been determined. It was previously demonstrated that EGCG blocks aryl hydrocarbon receptor (AhR)-mediated transcription induced by the potent carcinogen 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Unlike other AhR antagonists that directly bind to the AhR, EGCG inhibits AhR-mediated transcription by binding to hsp90. We hypothesize that EGCG exerts anti-AhR and anti-cancer effects by acting as an hsp90 inhibitor. Using proteolytic footprinting, immunoprecipitation, and an ATP-agarose pull-down assay, EGCG was found to directly modulate the conformation of hsp90 and bind at or near to a C-terminal ATP binding site. Hsp90 chaperone function, as assessed by its ability to mediate refolding of denatured luciferase, was inhibited by EGCG treatment. Hsp90 dimerization, which occurs at the C-terminal end, was also inhibited by EGCG treatment. Co-immunoprecipitation studies showed that EGCG stabilizes an AhR complex that includes hsp90 and XAP2 (hepatitis B virus X-associated protein 2), and decreases the association of aryl hydrocarbon nuclear translocator (Arnt) with ligand-activated AhR. Thus, EGCG, through its ability to bind to hsp90, blocks AhR response element (AhRE) recognition. These studies indicate a novel mechanism whereby EGCG inhibits ligand-induced AhRE binding and AhR-mediated transcriptional activity. In EGCG-treated human ovarian carcinoma SKOV3 cells, decreased levels of several cancer-related hsp90 client proteins, such as ErbB2, Raf-1 and phospho-AKT were observed. EGCG also modified the association of hsp90 with several cochaperones. Overall, these data indicate that EGCG is a novel hsp90 inhibitor. Further studies are needed to determine if this has a role in the anti-tumor actions of EGCG.
登录
查看更多内容
影响因子：
4.8
作者：
Bell, DR;Poland, A
通讯作者：
Poland, A
影响因子：
4.8
作者：
Marcu, MG;Chadli, A;Neckers, LM
通讯作者：
Neckers, LM
影响因子：
4.8
作者：
Kweon, Mee-Hyang;Adhami, Vaqar Mustafa;Mukhtar, Hasan
通讯作者：
Mukhtar, Hasan
影响因子：
4.8
作者：
Garnier, C;Lafitte, D;Peyrot, V
通讯作者：
Peyrot, V
影响因子：
2.9
作者：
Hartson, SD;Thulasiraman, V;Matts, RL
通讯作者：
Matts, RL