TIMP3: A Molecular Target of Green Tea Polyphenols

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 DESCRIPTION (provided by applicant): The overall goals of this proposal is to understand the mechanisms by which green tea polyphenols and its major constituent (-)-epigallocatechin-3-gallate inhibits prostate cancer metastasis. Consumption of green tea polyphenols (GTP) is effective in the development and could delay the progression of prostate cancer at its outset. However, the molecular mechanism(s) by which green tea polyphenols and its major constituent, epigallocatechin-3-gallate (EGCG) suppresses the metastatic process has not been completely understood. Metastasis is a complex multistep process that involves degradation of extracellular matrix through induction of proteolytic enzymes viz. matrix metalloproteinases (MMPs) and downregulation of their binding partner tissue inhibitor of metalloproteinases (TIMPs) critical for invasion and dissemination of malignant cells. Our preliminary studies demonstrate that GTP/EGCG-mediated tumor cell invasion correlate with decrease in MMP-2/9 expression along with concomitant increase in TIMP-3 in tumor cells. Based on our exciting preliminary results we hypothesize that GTP/EGCG-mediated re-expression of TIMP-3 is a critical mechanism wherein GTP/EGCG inhibits acquisition of invasiveness by prostate cancer cells and prevents 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 shown to be associated with an aggressive tumor phenotype and poor disease-free survival. Under the proposed specific aim 1 we will elucidate the molecular mechanism(s) by which GTP/EGCG upregulates TIMP-3 and suppress invasiveness in prostate cancer cells. Through experiments outlined in specific aim 2, we plan to determine the in vivo effects of GTP/EGCG in upregulating TIMP-3 and preventing metastasis in preclinical models. 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 reduces metastatic incidence in pre-clinical models. We plan to use an orthotopic implantation tumor model in castrated nu/nu mice which forms primary tumor in the organ and metastasizes to the bone and an intracardiac model of tumor metastasis using SCID mice which home tumors to various soft tissue. These studies will provide mechanistic basis and novel biomarkers for clinical investigation of GTP/EGCG in the prevention of metastasis at early stages thereby reducing the mortality and increase survivorship in prostate cancer patients suffering with recurrent form of the disease.