ACETYLCHOLINE AND NICOTINIC RECEPTORS IN LUNG CANCER

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 我们实验室最近的研究表明，在呼吸道上皮细胞、肺神经内分泌细胞(PNEC)和肺II型细胞中都有高水平的尼古丁受体(NAChR)和M受体(MAChR)。由于这些细胞类型分别与鳞状细胞癌(SCC)、小细胞肺癌(SCLC)、支气管肺泡癌(BAC)的起源有关，因此这些肿瘤很可能也会表达nAChR和mAChR。由于这些受体的激活会导致细胞内钙离子的增加，它们的激活通常会刺激细胞生长。更重要的是，我们实验室最近观察到，这些细胞类型还产生乙酰胆碱，这是nAChR和mAChR的配体。这表明肺癌是一个自分泌循环，在这个循环中，肺癌通过分泌乙酰胆碱来刺激自身生长。虽然尼古丁受体在小细胞肺癌中的表达已经被研究过，而且尼古丁已经被明确地证明可以刺激小细胞肺癌的生长，但我们观察到小细胞肺癌可能产生乙酰胆碱，从而调节自身的生长，这是一个新的令人兴奋的观察结果。因此，外源性配体(即吸烟产生的尼古丁)如何与内源性配体(乙酰胆碱)的促生长作用相互作用成为一个非常重要的问题。因此，本研究的目的是确定SCLC、SCC和BAC是否表达乙酰胆碱、nAChR和mAChR，进而确定胆碱能信号拮抗剂是否有可能为阻断肺癌的生长和发展提供新的途径。本年度的进展表明，M3毒扁豆碱拮抗剂具有抑制肺癌生长的潜在效用。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Recent studies from our laboratory have demonstrated high levels of nicotinic receptors (nAChR) and muscarinic receptors (mAChR) in airway epithelial cells, pulmonary neuroendocrine cells (PNEC) and pulmonary type II cells. Since these cell types are related to the origin of squamous cell carcinomas (SCC), small cell lung carcinomas (SCLC), bronchoalveolar carcinomas (BAC), respectively, it is highly likely that these carcinomas will also express nAChR and mAChR. Since activation of these receptors leads to increased intracellular cellular calcium, their activation typically stimulates cellular growth. Adding further significance is the recent observation from our laboratory that these cell types also make acetylcholine, the ligand for both nAChR and mAChR. This suggests an autocrine loop in which lung cancers secrete acetylcholine to stimulate their own growth. While the expression of nicotinic receptors in SCLC has been previously studied and nicotine has been clearly shown to stimulate growth of SCLC, our observation that SCLC may make acetylcholine and hence modulate their own growth is a new and exciting observation. Hence, how exogenous ligand (i.e., nicotine from smoking) then interacts with the growth promoting effects of endogenous ligand (acetylcholine) becomes a very important question. Thus the purpose of this study is to determine if SCLC, SCC and BAC express acetylcholine, nAChR and mAChR and to then determine the potential for antagonists of cholinergic signaling to provide new approaches to blocking the growth and development of lung cancer. Progress in the current year has demonstrated potential utility for M3 muscarinic antagonists to inhibit lung cancer growth.