Neurotransmitter Receptors and Lung Cancer

H.M. Schuller
College of Veterinary Medicine
University of Tennessee
Knoxville, TN

Lung cancer is the leading cause of cancer deaths in industrialized nations and demonstrates a strong etiologic link with smoking. Among those who smoke, individuals with a history of chronic respiratory tract disease are at a particularly high risk to develop lung cancer. We decided to study the autonomic regulation of cell proliferation in different histologic lung cancer types, and to explore how such regulatory pathways might be modulated by factors associated with chronic respiratory tract diseases. Using a panel of human lung cancer cell lines in assays for the identification of neurotransmitter receptors and assessment of cell proliferation, we found that the growth of small cell lung cancer is under parasympathetic control via an alpha-bungarotoxin-sensitive neuronal nicotinic acetylcholine receptor. Exposure of tumor cells in an environment of high carbon dioxide (10-15%) to nicotine or its carcinogenic derivative 4 (methyl-nitrosamino)- 1- (3-pyridyl)-1-butanone (NNK) resulted in ligand binding to this receptor and stimulation of cell proliferation via activation of an autocrine serotonergic loop. No proliferative response to nicotine or NNK was observed in cells maintained in a physiological CO2 concentration (5%). Cells exposed to 10% CO2 alone responded with secretion of serotonin and cell proliferation to a lesser extent than cells exposed simultaneously to this CO2 concentration and nicotine or NNK. We conclude that CO2 concentrations comparable to those found in the mildly diseased lung sensitize small cell lung cancer by an as yet unidentified mechanism to the mitogenic effects of cholinergic receptor stimulation by nicotine and NNK. In a second series of experiments, we showed that the growth of peripheral adenocarcinoma cells is regulated by a betaadrenergic receptor. Binding of agonists to this receptor resulted in activation of cyclic AMP and cell proliferation. Likewise, theophylline, which causes an intracellular accumulation of cAMP, stimulated the proliferation of these cells. Beta-adrenergic agonists and theophylline are the active ingredients of most broncho-dilating agents which are widely used for the therapy of chronic respiratory tract diseases. Accordingly, our findings suggest that these therapeutics may be a risk factor for the development of peripheral adenocarcinoma.