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Inhibition of Cholinergic Signaling Causes Apoptosis in Human Bronchioalveolar Carcinoma
Biochemistry and Microbiology
  • Jamie K. Lau, Marshall University
  • Kathleen C. Brown, Marshall University
  • Brent A. Thornhill, Marshall University
  • Clayton M. Crabtree, Marshall University
  • Aaron M. Dom, Marshall University
  • Theodore R. Witte, Marshall University
  • W. Elaine Hardman, Marshall University
  • Christopher A. McNees, Marshall University
  • Cody A. Stover, Marshall University
  • A. Betts Carpenter, Marshall University
  • Haitao Luo
  • Yi C. Chen
  • Brandon S. Shiflett, Marshall University
  • Piyali Dasgupta, Marshall University
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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.

This article first appeared in the February 15, 2013 issue of Cancer Research, the member magazine of the American Association for Cancer Research, and is reprinted with permission.

Final version can be found at:

©2013 American Association for Cancer Research. All rights reserved.

Citation Information
Lau JK, Brown KC, Thornhill BA, et al. Inhibition of cholinergic signaling causes apoptosis in human bronchioalveolar carcinoma. Cancer Res 2013;73(4):1328-1339.