Green tea polyphenols (GTP) and its major constituent, epigallocatechin-3-gallate (EGCG) has been associated with reduced risk of prostate cancer progression and emerged as a promising suppressor of metastasis. Our published study (Gupta et al. Proc. Natl. Acad. Sci. USA 98:10350-5, 2001) has shown that oral consumption of green tea polyphenols by transgenic mice [the TRAMP mouse model (transgenic adenocarcinoma of the mouse prostate)] genetically predisposed to developing prostate cancer, at doses readily achievable in humans, results in significant inhibition of primary tumor and completely prevented metastases to distant-site organs. Nonetheless, the mechanism of action of green tea polyphenols in blocking the metastatic process in cancer cells remains largely unknown. Based on the results of our preliminary studies we hypothesize that GTP/EGCG-mediated re-expression of Tissue Inhibitor of Metalloproteinases (TIMP)-3 is a critical mechanism wherein GTP/EGCG inhibits invasion of prostate cancer cells thereby preventing tumor metastasis. TIMP-3 directly binds to the catalytic domain of matrix metalloproteinase (MMP-2 and -9) in 1:1 stoichiometry, which are key enzymes involved in the dissolution of basement membrane. Low level of TIMP-3 protein expression has been associated with an aggressive tumor phenotype and poor disease-free survival. Under the proposed specific aim 1 we will investigate the epigenetic mechanism(s) by which GTP/EGCG reactivates TIMP-3 and suppress invasiveness in prostate cancer cells.
Specific aim 2 will determine the in vivo effects of GTP/EGCG in reactivating TIMP-3 and preventing metastasis. The hypothesis is that in vivo supplementation of GTP/EGCG could effectively increase TIMP-3 expression through global modification in histone proteins and specific alterations at the TIMP-3 promoter significantly reducing metastatic cascade in pre-clinical model. We plan to use an orthotopic implantation of C4-2B tumor cells in castrated nu/nu mice which forms primary tumor in the organ and metastasizes to the bone and invades local tissue including lymph nodes and liver. These studies will provide mechanistic basis of understanding the effect of GTP/EGCG in the prevention of prostate cancer metastasis.
Metastatic spread of prostate tumors remains the major cause of death and greatest barrier to cancer cure. We have previously shown that oral consumption of green tea polyphenols by transgenic mice genetically predisposed to developing prostate cancer, at doses readily achievable in humans, results in significant inhibition of primary tumor and completely prevented metastases to distant organs. Given the promise of green tea polyphenols (GTP) and its major polyphenolic constituent, epigallocatechin-3-gallate (EGCG) as a safe, efficacious, and cost-effective anticancer agent, it is imperative to understand the molecular mechanism by which GTP/EGCG inhibits prostate cancer metastasis. This application will provide mechanistic understanding and information about green tea polyphenols in suppressing metastasis and could be recommended for clinical trials.