Effects of chronic nicotine on the autocrine regulation of pancreatic cancer cells and pancreatic duct epithelial cells by stimulatory and inhibitory neurotransmitters
Effects of chronic nicotine on the autocrine regulation of pancreatic cancer cells and pancreatic duct epithelial cells by stimulatory and inhibitory neurotransmitters
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DOI：
10.1093/carcin/bgs229
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发表时间：
2012-09-01
期刊：
影响因子：
4.7
通讯作者：
Schuller, Hildegard M.
中科院分区：
文献类型：
--
作者：
Al-Wadei, Mohammed H.;Al-Wadei, Hussein A. N.;Schuller, Hildegard M.
胰腺导管腺癌（PDAC）的死亡率接近100%。吸烟是一个记录在案的风险因素。然而，吸烟相关的胰腺癌发生机制知之甚少。我们已经表明，尼古丁与PDAC和胰管上皮细胞中表达亚基7、3和5的烟碱乙酰胆碱受体（nAChR）的结合触发了这些细胞产生神经递质去甲肾上腺素和肾上腺素。反过来，这种自分泌儿茶酚胺回路通过β-肾上腺素能受体下游的环腺苷3 '，5'-单磷酸依赖性信号传导显著刺激细胞增殖。然而，观察到的反应仅代表对单剂量尼古丁的急性细胞反应，而吸烟者的尼古丁暴露是慢性的。使用PDAC细胞系BxPC-3和Panc-1和永生化胰管上皮细胞系HPDE 6-C7，我们目前的实验揭示了在预暴露于尼古丁7天的细胞中nAChR驱动的自分泌儿茶酚胺调节环的显著致敏作用。由此产生的儿茶酚胺产生的增加与信号蛋白ERK、CREB、Src和AKT的磷酸化的显著诱导、nAChR亚基3、4、5和7的蛋白表达的上调以及3-（4，5-二甲基噻唑-2-基）-2，5-二苯基溴化四氮唑和细胞迁移测定中对尼古丁的反应性增加相关。所有三种细胞系都产生抑制性神经递质-氨基丁酸，这种活性受到42 nAChR基因敲低的抑制，并通过受体脱敏受到慢性尼古丁的抑制。所有观察到的慢性尼古丁的不良反应被逆转的细胞与-氨基丁酸的治疗，这表明这种代理的潜在有用性，改善吸烟者的PDAC干预策略。
Pancreatic ductal adenocarcinoma (PDAC) has a mortality rate near 100%. Smoking is a documented risk factor. However, the mechanisms of smoking-associated pancreatic carcinogenesis are poorly understood. We have shown that binding of nicotine to nicotinic acetylcholine receptors (nAChRs) expressing subunits 7, 3 and 5 in PDAC and pancreatic duct epithelial cells in vitro triggered the production of the neurotransmitters noradrenaline and adrenaline by these cells. In turn, this autocrine catecholamine loop significantly stimulated cell proliferation via cyclic adenosine 3',5'-monophosphate-dependent signaling downstream of beta-adrenergic receptors. However, the observed responses only represent acute cellular reactions to single doses of nicotine whereas nicotine exposure in smokers is chronic. Using the PDAC cell lines BxPC-3 and Panc-1 and immortalized pancreatic duct epithelial cell line HPDE6-C7, our current experiments reveal a significant sensitization of the nAChR-driven autocrine catecholamine regulatory loop in cells pre-exposed to nicotine for 7 days. The resulting increase in catecholamine production was associated with significant inductions in the phosphorylation of signaling proteins ERK, CREB, Src and AKT, upregulated protein expression of nAChR subunits 3, 4, 5 and 7 and increased responsiveness to nicotine in 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide and cell migration assays. All three cell lines produced the inhibitory neurotransmitter -aminobutyric acid, an activity inhibited by gene knockdown of the 42nAChR and suppressed by chronic nicotine via receptor desensitization. All of the observed adverse effects of chronic nicotine were reversed by treatment of the cells with -aminobutyric acid, suggesting the potential usefulness of this agent for the improvement of PDAC intervention strategies in smokers.