Activated cholinergic signaling provides a target in squamous cell lung carcinoma.
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.
Song
Pingfang
P
Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Sciences University, Beaverton, Oregon, USA.
Sekhon
Harmanjatinder S
HS
Fu
Xiao Wen
XW
Maier
Michelle
M
Jia
Yibing
Y
Duan
Jie
J
Proskosil
Becky J
BJ
Gravett
Courtney
C
Lindstrom
Jon
J
Mark
Gregory P
GP
Saha
Saurabh
S
Spindel
Eliot R
ER
D000109:Acetylcholine / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001572:Benzofurans / Q000494:pharmacology; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism / Q000517:prevention & control; D049109:Cell Proliferation; D002478:Cells, Cultured; D002795:Choline O-Acetyltransferase / Q000235:genetics* / Q000378:metabolism; D004594:Electrophysiology; D058851:GPI-Linked Proteins; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000517:prevention & control; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009538:Nicotine / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011759:Pyrrolidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D043587:Receptor, Muscarinic M3 / Q000235:genetics* / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D050494:Vesicular Acetylcholine Transport Proteins / Q000235:genetics* / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D001572:Benzofurans; D058851:GPI-Linked Proteins; C485626:LYNX1 protein, human; D008562:Membrane Glycoproteins; D018727:Muscarinic Antagonists; D011759:Pyrrolidines; D012333:RNA, Messenger; D043587:Receptor, Muscarinic M3; D011978:Receptors, Nicotinic; C493459:SLC18A3 protein, human; D050494:Vesicular Acetylcholine Transport Proteins; D009538:Nicotine; C101207:darifenacin; D002795:Choline O-Acetyltransferase; D000109:Acetylcholine; D002118:Calcium