NNK, Beta-Adrenergic AA Release and Lung Cancer

NNK、β-肾上腺素能 AA 释放与肺癌

• 批准号: 6721254
• 负责人: Hildegard M. Schuller
• 金额: $ 29万
• 依托单位: UNIVERSITY OF TENNESSEE KNOXVILLE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6721254
• 关键词: DNA replication; adenocarcinoma; arachidonate; beta adrenergic receptor; binding sites; biological signal transduction; cell line; chemical carcinogenesis; enzyme activity; epithelium; glutathione transferase; guanine nucleotide binding protein; lung neoplasms; mitogen activated protein kinase; neoplasm /cancer genetics; nicotine; nitrosamines; nucleic acid biosynthesis; polymerase chain reaction; protein isoforms; radiotracer; receptor expression; tissue /cell culture; transfection /expression vector; western blottings

DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer death in the United States. Pulmonary adenocarcinoma (PAC) accounts for about 60 percent of all lung cancer cases with a mortality of >95 percent within one year of diagnosis. The long-term goal of this project is to identify novel molecular targets involved in the growth regulation of PAC and their normal cells of origin (small airway epithelia, SAE), the genetic make-up of which may determine susceptibility to smoking-associated PAC, and to identify the nature of changes to components of this pathway(s) caused by the nicotine-derived carcinogenic nitrosamine NNK. Our data provide evidence that the growth of human PAC cell lines and SAE is under beta-adrenergic control via the beta-adrenergic receptor-mediated release of arachidonic acid (AA). Furthermore, we have shown that NNK is a high affinity agonist for beta1 and beta2-adrenergic receptors and stimulates this AA-dependent mitogenic pathway. Based on these findings, we propose the following specific aims. 1. To determine if beta1 or beta2 or both of these adrenergic receptors mediate the observed AA-dependent stimulation of DNA synthesis, and to characterize the downstream effectors of these pathways. 2. To determine which products of the AA cascade are formed in untreated cells and in response to NNK, which of these products stimulate DNA synthesis, and what downstream effectors are activated by these products.

描述（由申请人提供）：肺癌是癌症的主要原因 死亡在美国。肺腺癌（PAC）约占 60%的肺癌病例死亡率> 95%， 年诊断。该项目的长期目标是确定新的 PAC生长调控中的分子靶点及其正常表达 起源细胞（小气道上皮细胞，SAE），其遗传组成可能 确定对吸烟相关PAC的敏感性，并确定其性质 由尼古丁衍生的 致癌亚硝胺NNK。我们的数据表明， 人PAC细胞系和SAE是在β-肾上腺素能控制下，通过 β-肾上腺素能受体介导的花生四烯酸（AA）释放。 此外，我们已经证明NNK是β 1的高亲和力激动剂， β 2-肾上腺素能受体，并刺激这种AA依赖性促有丝分裂途径。 根据这些发现，我们提出了以下具体目标。 1.为了确定β 1或β 2或这两种肾上腺素能受体是否介导 观察到的AA依赖性DNA合成刺激，并表征 这些通路的下游效应物。 2.确定未处理细胞中形成的AA级联反应产物 以及响应于NNK，这些产物中的哪些刺激DNA合成，以及 这些产品激活了哪些下游效应物。