Activated cholinergic signaling represents a new molecular target in the therapy of human bronchioalveolar carcinoma

Bronchioalveolar carcinomas (BACs) are highly aggressive tumors that are relatively chemoresistant and show an etiological association with smoking. Nicotine, the major active and addictive component of cigarettes, has been shown to accelerate cell proliferation and angiogenesis through nicotinic acetylcholine receptors (nAChRs). Acetylcholine (ACh) can act as an autocrine growth factor in small cell lung cancer and squamous cell carcinoma; however, the role of this proliferative cholinergic loop in BACs is unknown. We show for the first time that nicotine induces the secretion of ACh from human lung BACs in a dose‐dependent manner via α7‐ and β3‐containing‐nAChRs and has little to no effect on ACh production in normal epithelial cells. Western blotting analysis indicates that proteins involved in ACh signaling pathways, vesicular acetylcholine transporter (VAChT), choline transporter 1 (CHT1) and acetylecholinesterase (AChE) are expressed on human BACs. Finally, VAChT and CHT1 inhibitors caused robust apoptosis of BAC cells treated with nicotine. Our observations raise the possibility that components of the ACh‐signaling axis may represent novel molecular targets for lung BAC therapy.