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

绿茶通过刺激膜联蛋白 1 靶向 NSCLC 中的 COX-2/PGE2 和 EFGR 通路

• 批准号: 7321046
• 负责人: QING-YI LU
• 金额: $ 7.7万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7321046
• 关键词: Affect; Annexins; Anti-Inflammatory Agents; Anti-inflammatory; Benzo(a)pyrene; Biopsy; Bronchoalveolar Lavage Fluid; Cancer Etiology; Cancer cell line; Carcinogens; Cell Line; Cessation of life; Chemoprevention; Chemopreventive Agent; Clinical; Cytosolic Phospholipase A2; Data; Dietary Component; Dinoprostone; EGF gene; Eicosanoid Production; Epidermal Growth Factor Receptor; Epigallocatechin Gallate; Future; Green tea; HTATIP gene; Hypoxia; Incidence; Inflammatory; Investigation; Lipids; Literature; Lung; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Mediator of activation protein; Mitogen-Activated Protein Kinases; Molecular Target; Morbidity - disease rate; Mus; Neoplasm Metastasis; New Agents; Non-Small-Cell Lung Carcinoma; PLA2G4A gene; Pathogenesis; Pathway interactions; Patients; Physiological; Phytochemical; Prevention; Property; Prostaglandin-Endoperoxide Synthase; Proto-Oncogene Proteins c-akt; Range; Receptor Activation; Research; Research Personnel; Risk; Signal Pathway; Stimulation of Cell Proliferation; Stimulus; Structure of parenchyma of lung; Surrogate Endpoint; Survival Rate; Testing; Therapeutic; Therapeutic Effect; Tobacco smoke; Toxic effect; United States; Up-Regulation; Vitamins; Work; angiogenesis; base; carcinogenesis; cell growth; cell motility; cyclooxygenase 1; cyclooxygenase 2; design; human PLA2G4A protein; lung cancer prevention; lung carcinogenesis; mortality; novel strategies; polyphenol; prevent; research study; statistics; tumor growth

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.

描述（由申请人提供）： 肺癌是美国癌症相关死亡的最常见原因，2006年估计有162，246例死亡。尽管对肺癌进行了深入的研究，但接受治疗的患者的5年和10年总生存率分别仅为14%和8%。这些统计数据强调了需要确定新的方法和新的药物来治疗和预防肺癌。使用维生素补充剂预防肺癌的传统方法总体上不成功。新的策略采用靶向已知促进癌发生的关键途径的药理学试剂，包括涉及环氧合酶-2（考克斯-2）和表皮生长因子受体（EGFR）的那些。考克斯-2衍生的生物活性脂质，包括前列腺素E2（PGE 2），是重要的炎症介质，其通过刺激细胞增殖、侵袭和血管生成来促进肿瘤生长和转移。最近的工作已经证明了考克斯-2/PGE 2和EGFR途径之间的显著串扰。植物化学物质是天然存在的化合物，具有广泛的生理作用和一般低毒性。这些天然化合物之一是绿色茶多酚，其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。基于我们的初步数据和现有文献，我们假设来自绿色茶的多酚类化合物抑制考克斯-2/PGE 2和EGFR途径，至少部分地通过诱导膜联蛋白1介导。为了验证我们的假设，我们提出了以下具体目标：1。确定绿色茶对肺癌细胞系中考克斯-2、PGE 2、cPLA 2表达的抑制作用，并研究这些抑制作用是否由膜联蛋白1介导;和2.确定绿色茶对同一组细胞系中EGFR活化和EGFR下游靶蛋白激酶B（PKB或AKT）和促分裂原活化蛋白激酶（MAPK）的抑制作用，并研究这些抑制作用是否由膜联蛋白1介导。整个绿色茶提取物被选为测试化合物，这是由于我们的团队和其他研究人员在肺癌和其他癌症的背景下产生的初步数据。本申请中设计的实验将阐明绿色茶是否靶向考克斯-2/PGE 2和EGFR途径，这在肺癌预防和治疗中至关重要。我们的研究将集中在绿色茶抑制类花生酸的产生和导致细胞运动抑制的信号通路。这些研究结果将为未来研究饮食和分子靶向化学预防提供理论基础，旨在降低肺癌的发病率，发病率和死亡率。