Activated cholinergic signaling provides a target in squamous cell lung carcinoma

Pingfang Song, Harmanjatinder S. Sekhon, Wen Fu Xiao, Michelle Maier, Yibing Jia, Jie Duan, Becky J. Proskosil, Courtney Gravett, Jon Lindstrom, Gregory P. Mark, Saurabh Saha, Eliot R. Spindel

Research output: Contribution to journalArticle

90 Scopus citations

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 α5 and β3 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.

Original languageEnglish (US)
Pages (from-to)4693-4700
Number of pages8
JournalCancer Research
Volume68
Issue number12
DOIs
StatePublished - Jun 15 2008

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Song, P., Sekhon, H. S., Xiao, W. F., Maier, M., Jia, Y., Duan, J., Proskosil, B. J., Gravett, C., Lindstrom, J., Mark, G. P., Saha, S., & Spindel, E. R. (2008). Activated cholinergic signaling provides a target in squamous cell lung carcinoma. Cancer Research, 68(12), 4693-4700. https://doi.org/10.1158/0008-5472.CAN-08-0183