Activated cholinergic signaling provides a target in squamous cell lung carcinoma
Activated cholinergic signaling provides a target in squamous cell lung carcinoma
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DOI：
10.1158/0008-5472.can-08-0183
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发表时间：
2008-06-15
期刊：
影响因子：
11.2
通讯作者：
Spindel, Eliot R.
中科院分区：
文献类型：
--
作者：
Song, Pingfang;Sekhon, Harmanjatinder S.;Spindel, Eliot R.
外源性尼古丁与烟碱型乙酰胆碱（ACh）受体（nAChR）的结合以及内源性ACh与nAChR和毒蕈碱型ACh受体（mAChR）的结合刺激小细胞和非小细胞肺癌的生长。了解胆碱能信号在肺癌中是如何上调的可能会提出新的治疗方法。28例鳞状细胞肺癌（SCC）的分析显示，α 5和β 3 uAChR mRNA水平升高，ACh水平升高与胆碱乙酰转移酶mRNA水平升高和胆碱酯酶mRNA水平降低相关。Lynx 1，一种nAChR活性的变构抑制剂，在SCC中也减少。因此，胆碱能信号在SCC中广泛增加，这是由受体水平增加、配体水平增加和受体抑制剂水平降低引起的。部分解释了胆碱能上调看到SCC，孵育的H520 SCC细胞系与尼古丁增加乙酰胆碱分泌水平，增加表达的乙酰胆碱受体，并通过电生理记录测量，增加活性的表达的乙酰胆碱受体。与这些作用一致，尼古丁刺激H520细胞的增殖。阻断尼古丁和ACh对肺癌生长的增殖作用的一种方法可能是通过M3 mAChR拮抗剂，其可以限制由烟碱和毒蕈碱信号传导引起的有丝分裂原活化蛋白激酶的活化。这是用M3选择性毒蕈碱拮抗剂达非那新测试的。达非那新在体外阻断尼古丁刺激的H520生长，在体内也阻断H520在裸鼠中的生长。因此，胆碱能信号在SCC中广泛上调，阻断胆碱能信号可以限制SCC的基础和尼古丁刺激的生长。
The binding of exogenous nicotine to nicotinic acetylcholine (ACh) receptors (nAChR) and the binding of endogenous ACh to both nAChR and muscarinic ACh receptors (mAChR) stimulate growth of both small cell and non-small cell lung carcinomas. Understanding how cholinergic signaling is up-regulated in lung cancer may suggest new therapeutic approaches. Analysis of 28 squamous cell lung carcinomas (SCC) showed increased levels of alpha 5 and beta 3 uAChR mRNA and increased levels of ACh associated with increased levels of choline acetyltransferase mRNA and decreased cholinesterase mRNAs. Lynx1, an allosteric inhibitor of nAChR activity, was also decreased in SCC. Thus, cholinergic signaling is broadly increased in SCC caused by increased levels of receptors, increased levels of ligands, and decreased levels of receptor inhibitors. Partially explaining the cholinergic up-regulation seen in SCC, incubation of the H520 SCC cell line with nicotine increased levels of ACh secretion, increased expression of nAChR, and, as measured by electrophysiologic recording, increased activity of the expressed nAChR. Consistent with these effects, nicotine stimulated proliferation of H520 cells. One approach to blocking proliferative effects of nicotine and ACh on growth of lung cancers may be through M3 mAChR antagonists, which can limit the activation of mitogen-activated protein kinase that is caused by both nicotinic and muscarinic signaling. This was tested with the M3-selective muscarinic antagonist darifenacin. Darifenacin blocked nicotine-stimulated H520 growth in vitro and also blocked H520 growth in nude mice in vivo. Thus, cholinergic signaling is broadly up-regulated in SCC and blocking cholinergic signaling can limit basal and nicotine-stimulated growth of SCC.