NNK, Beta-Adrenergic AA Release and Lung Cancer

简介(申请人提供)：肺癌是导致癌症的主要原因 美国的死亡案例。肺腺癌(PAC)约占 所有肺癌病例中60%的死亡率为95% 诊断年份。这个项目的长期目标是确定新的 参与PAC生长调控的分子靶点及其正常 起源细胞(小气道上皮，SAE)，其基因组成可能 确定吸烟相关的PAC的易感性，并确定其性质 尼古丁衍生品引起的这一通路成分的变化(S) 致癌亚硝胺NNK。我们的数据提供了证据表明 人PAC细胞株和SAE受β-肾上腺素能调控 β肾上腺素能受体介导的花生四烯酸(AA)释放。 此外，我们还表明，NNK是一种高亲和力的β1激动剂和 β2-肾上腺素能受体，并刺激这种AA依赖的有丝分裂途径。 基于这些发现，我们提出了以下具体目标。 1.确定这些肾上腺素能受体是否通过β1或β2或两者共同介导 观察到的AA依赖对DNA合成的刺激作用，并表征 这些通路的下游效应器。 2.确定在未经处理的细胞中形成了哪些AA级联产物 作为对NNK的回应，这些产品中的哪一种可以刺激DNA合成，以及 这些产品激活了哪些下游效应器。

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.