Acetylcholine signaling pathway: A novel target for lung cancer in smokers

Abstract

The clinicopathological features of lung cancer in smokers is completely different from never‐smokers. Whereas lung cancer patients (who are never smokers) respond well to targeted therapies involving EGFR inhibitors and ALK kinase inhibitors, the response of these drugs in lung cancer patients who are smokers is poor. Nicotine is the addictive component of cigarette smoke. Nicotine (at concentrations present in the plasma of moderate smokers) accelerates the growth, angiogenesis and metastasis of lung cancers. The biological activity of nicotine is mediated by nicotinic acetylcholine receptors (nAChRs). The endogenous ligand for nAChRs in the lung is the neurotransmitter acetylcholine (ACh). ACh is known to be an autocrine growth factor for both SCLC and NSCLC. One of the ways that nicotine and cigarette smoke promote the growth of lung cancers is by promoting the production of ACh, which binds to its cognate receptor (on lung cancer cells) in an autocrine manner and induces the proliferation of lung cancer cells. The objective of the present study is to investigate the whether the ACh‐mitogenic signaling pathway are altered in human lung cancer. We show that levels three acetylcholine‐signaling proteins namely ChAT, VAChT and AChE are significantly altered in lung cancer occurring in active smokers. Small‐molecule regulators of these proteins suppress the growth of human lung cancer cells. Our studies will facilitate the identification of targeted therapies for the majority of lung cancer patients who are exposed to tobacco smoke.Support or Funding InformationFunding for our study was supported by an NIH R15‐AREA Grant (2R15CA161491‐02) and the West Virginia IDeA Network of Biomedical Research Excellence (WV‐INBRE) grant GM103434 (PI: Dr. G. Rankin). Furthermore, this study was supported in part by an Institutional Development grant (IDeA) Grant number P20GM104932 from the National Institute of General Medical Sciences (NIGMS) and the Research Core B of COBRE, a component of the National Institutes of Health (NIH)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.