Department of Pharmacology, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA.
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.
最近的病例对照临床研究表明，细支气管肺泡癌（BAC）与吸烟有关。香烟中的成瘾成分尼古丁通过烟碱型乙酰胆碱受体（nAChR）加速细胞增殖。在这项研究中，我们表明人 BAC 产生乙酰胆碱（ACh）并包含几种胆碱能因子，包括乙酰胆碱酯酶（AChE）、胆碱乙酰转移酶（ChAT）、胆碱转运蛋白 1（CHT1，SLC5A7）、囊泡乙酰胆碱转运体（VAChT，SLC18A3）和烟碱型乙酰胆碱受体（AChRs，CHRNAs）。尼古丁增加了人 BAC 中 ACh 的产生，ACh 是这些细胞的生长因子。尼古丁诱导的 ACh 产生是通过α7、α3β2 和β3-nAChR、ChAT 和 VAChT 途径介导的。我们观察到尼古丁上调了 ChAT 和 VAChT。因此，我们推测 VAChT 拮抗剂，如维拉米考尔，可能抑制人 BAC 的生长。维拉米考尔在细胞培养和裸鼠模型中诱导人 BAC 强烈凋亡。维拉米考尔对 EGF 或胰岛素样生长因子-II 诱导的人 BAC 生长没有任何影响。siRNA 介导的 VAChT 衰减逆转了维拉米考尔的凋亡活性。我们还观察到维拉米考尔在细胞死亡过程中抑制 Akt 磷酸化，而过表达组成型激活的 Akt 逆转了维拉米考尔的凋亡活性。综上所述，我们的结果表明，维拉米考尔等药物破坏尼古丁诱导的胆碱能信号可能在 BAC 治疗中具有应用前景。
