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.
Highlights
Lung cancer is the number one cause of cancer death in the United States with deaths in 2007 estimated to exceed 160,000 [1]
(SCLC) which accounts for approximately 14–20 percent of cases and non-small cell lung carcinoma (NSCLC) which accounts for the remaining cases
While the primary mechanism of smoking-induced carcinogenesis derives from carcinogens in smoke, recent data shows that nicotine and nitrosamines in smoke bind to nicotinic acetylcholine (ACh) receptors on lung cancers to stimulate growth and potentially tumor progression [4,5,6,7,8,9]
Summary
Lung cancer is the number one cause of cancer death in the United States with deaths in 2007 estimated to exceed 160,000 [1]. Normal bronchial epithelial cells express nAChR as part of a cholinergic autocrine loop [13,14,15,16] in which all proteins needed for cholinergic signaling are present including the ACh-synthesizing enzyme choline acetyltransferase (ChAT), the vesicular acetylcholine ACh transporter (VAChT), the highaffinity choline transporter CHT1, the ACh hydrolyzing enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), nicotinic acetylcholine receptors and muscarinic acetylcholine receptors (mAChR). We and others have demonstrated that the interaction of ACh with both nAChR and mAChR stimulates cell proliferation [11,17,18,19,20] and we have previously reported that SCLC express this cholinergic autocrine loop and that muscarinic antagonists can inhibit SCLC cell proliferation
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