Green tea polyphenols appear to be chemopreventive against certain cancers, including oral cancer; but how cancer cells succumb while normal cells survive this polyphenol exposure is not known. Lack of this information prevented clinical uses of polyphenols for oral cancer chemoprevention or treatment. The long-term goal of this investigation is to elucidate the signal pathways and mechanisms by which green tea polyphenols differentially target normal and malignant cells to direct protective or apoptotic effects. Preliminary data from our laboratories have demonstrated that normal epithelial cells express p57 (KIP2) in response to green tea polyphenols in a dose- and time-dependent manner. We propose a novel concept, that green tea polyphenols are able to activate two pathways: 1) a p57-mediated survival pathway, and/or 2) a caspase 3-dependent apoptosis pathway. The hypotheses to be tested is that p57 induction by green tea polyphenols in normal epithelial cells may serve an anti-apoptotic function, absence of the p57 response in malignant cells may result in induction of caspase 3-dependent apoptosis. The immediate goal of this proposal is to identify the survival or apoptotic genes that are regulated by green tea polyphenols. In this proposed project, the survival/apoptosis gene expression profile will be determined following green tea polyphenol exposure, in normal human epidermal keratinocytes and in human oral squamous cell carcinoma cells. Specifically, the levels of p57 expression induced by the most potent green tea polyphenol, (-)- epigallocatechin-3-gallate (EGCG), in normal human epithelial cells will be determined. Using RT-PCR, mRNA stability assay, Northern and Western blot analyses, the relationship between transcription/translation levels of p57 induction and the time/dose of EGCG will be established. The RNA samples at specific time points will be subjeted to gene array analysis and profiling. Not only will the expression profile of those genes that are either activated or suppressed by EGCG in normal or tumor cells, but promising cellular targets for future chemotherapeutic intervention may be identified. Data generated from this proposal may reveal novel drug targets for treatment of head and neck cancer.
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