Inhibition of cholinergic signaling causes apoptosis in human bronchioalveolar carcinoma

Abstract

Recent clinical studies show that bronchioalveolar carcinomas (BACs) are correlated with smoking. Nicotine, the major addictive component of cigarettes, accelerates cell proliferation through nicotinic acetylcholine receptors (nAChRs). Here we show that human BACs produce acetylcholine (ACh) and contain all of the cholinergic system proteins, including acetylcholinesterase (AChE), choline acetyltransferase (ChAT), choline transporter 1 (CHT1), vesicular acetylcholine transporter (VAChT) and nAChRs. Nicotine increases the production of ACh in human BACs. ACh acts as a growth factor for human BACs. We observed that nicotine upregulates 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 IGF‐II‐induced growth of human BAC's. The ablation of VAChT levels by siRNA methodology reversed the apoptotic activity of vesamicol. We also observed that vesamicol caused cell death by inhibiting Akt phosphorylation. The overexpression of constitutively active Akt reversed the apoptotic activity of vesamicol. Taken together, our data shows that disruption of nicotine‐induced cholinergic signaling by agents such as vesamicol may have applications in BAC therapy.