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

描述(由申请人提供)： 肺癌是美国最常见的癌症相关死亡原因，2006年估计有162,246人死亡。尽管对肺癌进行了密集的研究，但接受治疗的患者的5年和10年总存活率分别只有14%和8%。这些统计数据突出表明，需要确定治疗和预防肺癌的新方法和新制剂。使用维生素补充剂预防肺癌的传统方法总体上并不成功。新的策略使用了针对已知促进癌症发生的关键途径的药物，包括那些涉及环氧合酶-2(COX-2)和表皮生长因子受体(EGFR)的途径。COX-2衍生的生物活性脂质，包括前列腺素E2(PGE2)，是重要的炎性介质，通过刺激细胞增殖、侵袭和血管生成促进肿瘤的生长和转移。最近的研究表明，COX-2/PGE2和EGFR通路之间存在显著的串扰。植物化学物质是一种天然存在的化合物，具有广泛的生理作用，一般毒性较低。绿茶多酚是此类天然化合物之一，已被证明通过抑制环氧合酶和减少肿瘤生长而具有抗炎特性。根据我们的初步数据和现有文献，我们假设绿茶多酚化合物抑制COX-2/PGE2和EGFR通路，至少部分是通过膜联蛋白1的诱导。为了验证我们的假设，我们提出了以下具体目标：1.确定绿茶对肺癌细胞株COX-2、PGE2、cPLA2表达的抑制作用，并探讨这些抑制作用是否由膜联蛋白1介导；2.为了确定绿茶对同一组细胞系中EGFR激活及其下游靶蛋白激酶B(PKB或AKT)和丝裂原活化蛋白激酶(MAPK)的抑制作用，并探讨这些抑制作用是否由膜联蛋白1介导。鉴于我们团队和其他研究人员在肺癌和其他癌症方面的初步数据，选择整个绿茶提取物作为测试化合物。在这项应用中设计的实验将阐明绿茶是否同时针对COX-2/PGE2和EGFR途径，这两个途径在肺癌预防和治疗中至关重要。我们的研究将集中在绿茶对二十烷类化合物产生的抑制作用以及导致细胞运动抑制的信号通路。这些研究的结果将为未来旨在降低肺癌发病率、发病率和死亡率的饮食和分子靶向化学预防的研究提供理论基础。

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.