Activated Cholinergic Signaling Provides a Target in Squamous Cell Lung Carcinoma
Open accessPublished version of a preprint
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. [Cancer Res 2008;68(12):4693–700]
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Bronchial epithelium, squamous cell lung carcinoma, non-small-cell lung cancers, and BEP2D cells express α5 subunits.
“Bronchial epithelium, squamous cell lung carcinoma, non-small-cell lung cancers, and BEP2D cells express α5 subunits (108–110); but their partner subunits and functional states are not known.”
From Nicotine is a selective pharmacological chaperone of acetylcholine receptor number and stoichiometry. Implications for drug discovery (2009) · cites this paper as [110]
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- Authors
- Song, P., Sekhon, H. S., Fu, X. W., Maier, M., Jia, Y., Duan, J., Proskosil, B. J., Gravett, C., Lindstrom, J., Mark, G. P., Saha, S., & Spindel, E. R.
- Affiliations
- Oregon National Primate Research Center (US)
- 1Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Sciences University, Beaverton, Oregon;
- University of Pennsylvania (US)
- Oregon Health & Science University (US)
- Novartis (Switzerland) (CH)
- Venue
- Cancer Research
- Published
- 2008-06-15
- Volume
- 68
- Issue
- 12
- Pages
- 4693-4700
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC2865551
- OpenAlex
- W2047735189
- Cited by
- 141
- References
- 51
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 10 · 2023: 6 · 2022: 11 · 2021: 12 · 2020: 6 · 2019: 4 · 2018: 3 · 2017: 4 · 2016: 7 · 2015: 10 · 2014: 7 · 2013: 10 · 2012: 12
- FWCI
- 4.52
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Cancer Research (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (HL087710, R01HL087710)
- National Institute of Neurological Disorders and Stroke (NS11323, R01NS011323)
- National Center for Research Resources (P51RR000163, K01RR000163, RR-00163.)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Health Sciences › Medicine › Physiology › Smoking Behavior and Cessation
- Health Sciences › Medicine › Psychiatry and Mental health › Cancer, Stress, Anesthesia, and Immune Response
- Keywords
- lung squamous cell carcinoma, cholinergic neurotransmission, nicotinic acetylcholine receptors, muscarinic receptors, choline acetyltransferase, cholinesterase, Lynx1, nicotine, acetylcholine, M3 muscarinic receptor antagonist, darifenacin, mitogen-activated protein kinase, cell proliferation
- MeSH terms
- Acetylcholine, Animals, Benzofurans, Calcium, Carcinoma, Squamous Cell, Cells, Cultured, Choline O-Acetyltransferase, Electrophysiology, Humans, Lung, Lung Neoplasms, Male, Membrane Glycoproteins, Mice, Nude, Nicotine, Phosphorylation, Pyrrolidines, Receptors, Nicotinic, RNA, Messenger, Blotting, Western, Signal Transduction, Muscarinic Antagonists, Reverse Transcriptase Polymerase Chain Reaction, Receptor, Muscarinic M3, Adaptor Proteins, Signal Transducing, Cell Proliferation, Vesicular Acetylcholine Transport Proteins, Mice, GPI-Linked Proteins
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