NNK, Beta-Adrenergic AA Release and Lung Cancer

点击翻译按钮获取中文摘要

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.