Role of Nicotine in Lung Carcinogenesis

描述（申请人提供）：吸烟与肺癌发病有很强的相关性，统计上90%以上的肺癌患者是吸烟者。然而，由二手烟引起的肺癌尚不清楚。尼古丁是香烟的主要成分，在吸烟者的血液中含量很高。基于尼古丁的产品被广泛用于帮助戒烟和治疗临床慢性疼痛患者。研究表明，尼古丁与尼古丁乙酰胆碱受体（尼古丁acetylcholine receptor， nAChRs）结合，进一步激活多种细胞（包括肺上皮细胞、癌细胞和血管内皮细胞）中与丝裂原相关的信号通路。Bcl-2的抗凋亡活性也受到尼古丁处理的诱导。我们证明尼古丁激活Ras和蛋白激酶C （PKC）途径，导致细胞生长限制的破坏。然而，尼古丁在肺癌发生或发展中的作用机制仍有待阐明。因此，我们建议的长期目标是研究尼古丁在肺癌发生中的作用。这项研究将确定尼古丁介导的信号通路中的新成分，并将有助于改变目前尼古丁的使用。该提案的中心假设是尼古丁作为一种潜在的致癌物，可以调动细胞内生长相关的信号通路并拮抗凋亡信号，从而为肿瘤的发生创造一个宽松的环境。验证该假说的具体目的是：1)探讨尼古丁促进细胞生长的机制；2)确定尼古丁暴露如何扰乱G1细胞周期检查点；3)研究尼古丁介导的抗凋亡作用的分子机制。小鼠或大鼠肺上皮细胞和各种人类肺癌细胞将用于拟议的实验。我们对尼古丁的了解不仅为这种化合物的治疗用途提供了一个警告立场，而且还有助于开发治疗尼古丁成瘾或慢性疼痛停止的新策略。

DESCRIPTION (provided by applicant): Cigarette smoking is strongly correlated with onset of lung cancer and statistically more than 90% of lung cancer patients are smokers. However, lung cancer caused by second-hand smoking remains unknown. Nicotine is a major component of cigarettes and exists at high concentrations in the bloodstream of smokers. Nicotine-based products are widely used to aid smoking cessation and to treat patients clinically with chronic pain. Studies have shown that nicotine binds to nicotine acetylcholine receptors (nAChRs) and further activates several mitogen-related signaling pathways in various types of cells including lung epithelial and cancer cells and vascular endothelial cells. The anti-apoptotic activity of Bcl-2 is also induced by nicotine treatment. We demonstrated that nicotine activates Ras and protein kinase C (PKC) pathways, leading to the disruption of cell growth restriction. However, the mechanisms of nicotine in the onset or development of lung cancer remain to be elucidated. Therefore, our long-term objective of the proposal is to study the role of nicotine in lung carcinogenesis. Such study will identify novel components in nicotine-mediated signaling pathways and will help modifying the current usage of nicotine. The central hypothesis of the proposal is that nicotine acts as a potential carcinogen that can mobilize intracellular growth-related signal pathways and antagonize apoptotic signaling, which creates a permissive environment for tumorigenesis. The specific aims to test the hypothesis are: 1) to investigate the mechanisms of nicotine-mediated cell growth promotion; 2) to determine how nicotine exposure perturbs G1 cell cycle checkpoint; 3) to study the molecular mechanisms of nicotine-mediated anti-apoptotic action. Mouse or rat lung epithelial and various human lung cancer cells will be used in the proposed experiments. Our understanding of nicotine will not only offer a cautionary stance for the therapeutic use of this compound, but also help developing new stratigies for treating nicotine addiction or chronic pain cessation.