Green Tea Targets COX-2/PGE2 and EFGR Pathways in NSCLC via Stimulating Annexin 1

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DESCRIPTION (provided by applicant): Lung cancer is the most common cause of cancer-related death in the United States with estimated 162,246 deaths in 2006. Despite the intensive research on lung cancer, the 5- and 10-year overall survival rates for patients receiving treatment were only 14% and 8%, respectively. These statistics underlined the need to identify new approaches and new agents for the treatment and prevention of lung cancer. Traditional approaches to prevent lung cancer using vitamin supplements have been unsuccessful overall. New strategies employ pharmacologic agents that target key pathways known to promote carcinogenesis, including those involving cyclooxygenase-2 (COX-2) and epidermal growth factor receptors (EGFR). COX-2 derived bioactive lipids, including prostaglandin E2 (PGE2), are important inflammatory mediators that promote tumor growth and metastasis through stimulation of cell proliferation, invasion, and angiogenesis. Recent work has demonstrated significant crosstalk between the COX-2/ PGE2 and the EGFR pathways. Phytochemicals are naturally occurring compounds with a broad range of physiological actions and generally low toxicity. One of such natural compounds is green tea polyphenols that have been shown to possess anti-inflammatory properties via inhibition of cyclooxygenase and reduction of tumor growth. Based on our preliminary data and the available literature we hypothesize that polyphenolic compounds from green tea inhibit both COX-2/PGE2 and EGFR pathways mediated, at least in part, by the induction of annexin 1. To test our hypothesis we propose the following specific aims: 1. to determine the inhibitory effects of green tea on COX-2, PGE2, cPLA2 expressions in lung cancer cell lines, and to investigate whether these inhibitory effects are mediated by annexin 1; and 2. to determine the inhibitory effects of green tea on EGFR activation and the EGFR downstream targets protein kinase B (PKB or AKT) and mitogen-activated protein kinase (MAPK) in the same panel of cell lines, and to investigate whether these inhibitory effects are mediated by annexin 1. Whole green tea extract is chosen as a test compound due to the preliminary data our team and other researchers have generated in the context of lung and other cancers. The experiments designed in this application will elucidate whether green tea targets both COX-2/PGE2 and EGFR pathways, which are of critical importance in lung cancer prevention and treatment. Our studies will focus on the green tea in inhibition of eicosanoid production and the signaling pathways leading to the inhibition of cell motility. The results from the studies will provide rationale for future investigations on the dietary and molecular-targeted chemoprevention aimed to reduce the incidence, morbidity, and mortality of lung cancer.