Activated cholinergic signaling provides a target in squamous cell lung carcinoma.
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Song, Pingfang, Sekhon, Harmanjatinder S, Fu, Xiao Wen, Maier, Michelle, Jia, Yibing, Duan, Jie, Proskosil, Becky J, Gravett, Courtney, Lindstrom, Jon, Mark, Gregory P, Saha, Saurabh and Spindel, Eliot R (2008) Activated cholinergic signaling provides a target in squamous cell lung carcinoma. Cancer Research, 68 (12). pp. 4693-4700. ISSN 1538-7445
Abstract
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 alpha5 and beta3 nAChR 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.
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| Additional Information: | author can archive post-print (ie final draft post-refereeing); Authors final version may be deposited on institutional website/ repository if required by institution |
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| Date Deposited: | 14 Dec 2009 13:53 |
| Last Modified: | 14 Dec 2009 13:53 |
| URI: | https://oak.novartis.com/id/eprint/820 |