EGCG Inhibits AhR and Carcinogenesis by Modulating Hsp90

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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.