(-)-Epigallocatechin-3-gallate is a novel Hsp90 inhibitor.
Biochemistry
; 48(2): 336-45, 2009 Jan 20.
Article
em En
| MEDLINE
| ID: mdl-19113837
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Catequina
/
Proteínas de Choque Térmico HSP90
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Biochemistry
Ano de publicação:
2009
Tipo de documento:
Article
País de afiliação:
Estados Unidos