Inhibition of cholinergic signaling causes apoptosis in human bronchioalveolar carcinoma

Cancer Res. 2013 Feb 15;73(4):1328-39. doi: 10.1158/0008-5472.CAN-12-3190. Epub 2012 Dec 7.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholine / metabolism*
  • Adenocarcinoma, Bronchiolo-Alveolar / drug therapy*
  • Adenocarcinoma, Bronchiolo-Alveolar / metabolism
  • Adenocarcinoma, Bronchiolo-Alveolar / pathology
  • Animals
  • Apoptosis / drug effects*
  • Blotting, Western
  • Cell Line, Tumor
  • Cells, Cultured
  • Humans
  • Immunohistochemistry
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Male
  • Mice
  • Mice, Nude
  • Neuromuscular Depolarizing Agents / pharmacology
  • Phosphorylation / drug effects
  • Piperidines / pharmacology*
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA Interference
  • Signal Transduction / drug effects*
  • Vesicular Acetylcholine Transport Proteins / antagonists & inhibitors
  • Vesicular Acetylcholine Transport Proteins / genetics
  • Vesicular Acetylcholine Transport Proteins / metabolism
  • Xenograft Model Antitumor Assays


  • Neuromuscular Depolarizing Agents
  • Piperidines
  • Vesicular Acetylcholine Transport Proteins
  • vesamicol
  • Proto-Oncogene Proteins c-akt
  • Acetylcholine