Interactions of EGCG and Hsp90 in Oncogenesis
Several epidemiological studies and clinical trials have shown the effectiveness of green tea (GT) extract for the prevention of UV-induced skin injuries, oxidative DNA damage, as well as prostate cancer. Epigallocatechin-3-gallate (EGCG), a major antioxidant in GT, has been suggested to target several biomedically relevant molecules and disease-related cellular processes. However, the precise molecular and cellular mechanisms by which EGCG acts to modulate tumor growth have yet to be determined.
In the movie to the right, AhR, when not bound to a ligand, is present in the cytoplasm associated with two molecules of hsp90, as well as other proteins. Ligand binding initiates a cascade of events, including AhR translocation to the nucleus, release of hsp90, and dimerization with the AhR nuclear translocator (Arnt). The ligand bound AhR-Arnt complex recognize and bind to the AhR-response elements (ARE) located in the promoter region of responsive genes, and affect the transcription of those genes.
Through our work on the AhR, we have made the novel discovery that EGCG inhibits the function of the chaperone 90 kD heat shock protein (hsp90). This chaperone protein is known to regulate the activity of the AhR and a number of other transcription factors and proteins many of which are involved in oncogenic processes. Using a novel mouse model of human prostate cancer, our laboratory is studying the chemical and structural basis by which EGCG and similar molecules affect hsp90, and have a potential anti-tumorigenic effect.
Unlike many other AhR antagonists that interact directly with the AhR, EGCG appears to block AhR-mediated transcription by binding to hsp90 and preventing dissociation and subsequent DNA binding in the nucleus.
Ongoing Questions for the Lab:
- Does EGCG affect the levels and/or activity of particular hsp90 client proteins?
- How is prostatic carcinogenesis affected by EGCG?
- Does EGCG alter the level and/or function of hsp90 client proteins at a sensitive stage of prostate cancer development?
- Are there derivatives or structural analogues of EGCG that are more potent in block prostate cancer development?