Title: (-)-Epigallocatechin-3-gallate is a novel Hsp90 inhibitor.

Authors: Yin, Zhengyu; Henry, Ellen C; Gasiewicz, Thomas A

Published In Biochemistry, (2009 Jan 20)

Abstract: (-)-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 anticancer 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. Coimmunoprecipitation 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 antitumor actions of EGCG.

PubMed ID: 19113837

MeSH Terms: Animals; Binding Sites/genetics; Catechin/analogs & derivatives*; Catechin/metabolism; Catechin/pharmacology; Cell Line, Tumor; Chickens; Dimerization; Dose-Response Relationship, Drug; Glutathione Transferase/metabolism; HSP90 Heat-Shock Proteins/antagonists & inhibitors*; HSP90 Heat-Shock Proteins/genetics; HSP90 Heat-Shock Proteins/isolation & purification; Humans; Ligands; Mice; Models, Biological; Molecular Chaperones/antagonists & inhibitors; Molecular Chaperones/genetics; Peptide Mapping; Plasmids; Protein Binding/genetics; Protein Conformation/drug effects; Receptors, Aryl Hydrocarbon/metabolism; Recombinant Fusion Proteins/metabolism; Response Elements/drug effects; Tea/genetics; Time Factors; Transcription, Genetic/drug effects