Abstract
Recent case-controlled clinical studies show that bronchioalveolar carcinomas (BAC) are correlated with smoking. Nicotine, the addictive component of cigarettes, accelerates cell proliferation through nicotinic acetylcholine receptors (nAChR). In this study, we show that human BACs produce acetylcholine (ACh) and contain several cholinergic factors including acetylcholinesterase (AChE), choline acetyltransferase (ChAT), choline transporter 1 (CHT1, SLC5A7), vesicular acetylcholine transporter (VAChT, SLC18A3), and nACh receptors (AChRs, CHRNAs). Nicotine increased the production of ACh in human BACs, and ACh acts as a growth factor for these cells. Nicotine-induced ACh production was mediated by α7-, α3β2-, and β3-nAChRs, ChAT and VAChT pathways. We observed that nicotine upregulated ChAT and VAChT. Therefore, we conjectured that VAChT antagonists, such as vesamicol, may suppress the growth of human BACs. Vesamicol induced potent apoptosis of human BACs in cell culture and nude mice models. Vesamicol did not have any effect on EGF or insulin-like growth factor-II-induced growth of human BACs. siRNA-mediated attenuation of VAChT reversed the apoptotic activity of vesamicol. We also observed that vesamicol inhibited Akt phosphorylation during cell death and that overexpression of constitutively active Akt reversed the apoptotic activity of vesamicol. Taken together, our results suggested that disruption of nicotine-induced cholinergic signaling by agents such as vesamicol may have applications in BAC therapy.
Highlights
Bronchioalveolar carcinoma (BAC) is a subtype of lung adenocarcinoma arising from type II pneumonocytes in the lung
Immunoblotting experiments were carried out to examine the presence of AChE, choline acetyltransferase (ChAT), CHT1, and VAChT (Fig. 1B) in human bronchioalveolar carcinomas (BAC) cell lines and in human pulmonary alveolar epithelial cells (HPAEpiC)
We observed that human BAC cell lines, as well HPAEpiCs normal lung cells, express VAChT, ChAT, AChE, and CHT1
Summary
Bronchioalveolar carcinoma (BAC) is a subtype of lung adenocarcinoma arising from type II pneumonocytes in the lung. The World Health Organization revised its classification of BACs in 2004 to include lung adenocarcinomas, which grow in a lepidic fashion along the alveolar septa without invasion into the stroma, pleura, blood vessels, or lymphatics [1,2,3]. The incidence of pure BACs is about 4%; mixed subtypes, including BACs with stromal invasion and pulmonary adenocarcinoma with BAC-like morphologic features, account for almost 20% of all non–small cell lung cancers Authors' Affiliations: Departments of 1Pharmacology, Physiology, and Toxicology, 2Biochemistry and Microbiology, and 3Anatomy and Pathology, Joan C.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
