Pancreatic cancer cells and normal pancreatic duct epithelial cells express an autocrine catecholamine loop that is activated by nicotinic acetylcholine receptors α3, α5, and α7.
Pancreatic cancer cells and normal pancreatic duct epithelial cells express an autocrine catecholamine loop that is activated by nicotinic acetylcholine receptors α3, α5, and α7.
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DOI：
10.1158/1541-7786.mcr-11-0332
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发表时间：
2012-02
期刊：
影响因子：
--
通讯作者：
Schuller HM
中科院分区：
文献类型：
--
作者：
Al-Wadei MH;Al-Wadei HA;Schuller HM
胰腺癌是发达国家癌症死亡的第四大原因。吸烟是这种恶性肿瘤的一个既定的危险因素，但其潜在的机制知之甚少。先前的报道提供了证据表明，烟碱乙酰胆碱受体（nAChR）和β-肾上腺素能受体（β-AR）刺激胰腺癌细胞的生长和迁移。但迄今为止，尚未研究这两个受体家族在胰腺癌调控中的潜在合作。使用两种胰腺癌细胞系和永生化的胰腺导管上皮细胞在体外，我们目前的数据显示，所有三种细胞系在暴露于尼古丁时合成并释放儿茶酚胺神经递质去甲肾上腺素和肾上腺素，并且该活性受α3、α5和α7-nAChR调节。与这些儿茶酚胺作为β-AR激动剂的既定功能雅阁，β-AR拮抗剂普萘洛尔阻断尼古丁诱导的细胞增殖。尼古丁诱导的增殖也被α7-nAChR拮抗剂α-银环蛇毒素消除，而尼古丁响应的儿茶酚胺产生被α3、α5和α7-nAChR的基因敲低阻断。尼古丁激动剂乙酰胆碱、尼古丁及其亚硝化致癌衍生物NNK诱导CREB、ERK、Src和AKT的磷酸化，这些反应被普萘洛尔抑制。我们的研究结果确定了这个迄今未知的自分泌儿茶酚胺环作为胰腺癌中的重要调节级联反应，这可能证明是一个有前途的癌症干预新靶点。
Pancreatic cancer is the fourth leading cause of cancer deaths in developed countries. Smoking is an established risk factor for this malignancy but the underlying mechanisms are poorly understood. Previous reports have provided evidence that nicotinic acetylcholine receptors (nAChRs) and beta-adrenergic receptors (β-ARs) stimulate the growth and migration of pancreatic cancer cells. But a potential cooperation of these two receptor families in the regulation of pancreatic cancer has not been studied to date. Using two pancreatic cancer cell lines and immortalized pancreatic duct epithelia in vitro, our current data show, that all three cell lines synthesized and released the catecholamine neurotransmitters noradrenaline and adrenaline upon exposure to nicotine and that this activity was regulated by α3, α5, and α7-nAChRs. In accord with the established function of these catecholamines as β-AR agonists, nicotine-induced cell proliferation was blocked by the β-AR antagonist propranolol. Nicotine-induced proliferation was also abolished by the α7-nAChR antagonist α-bungarotoxin while catecholamine production in response to nicotine was blocked by gene knockdown of the α3, α5, and α7-nAChRs. The nicotinic agonists acetylcholine, nicotine, and its nitrosated carcinogenic derivative NNK induced the phosphorylation of CREB, ERK, Src and AKT and these responses were inhibited by propranolol. Our findings identify this hitherto unknown autocrine catecholamine loop as an important regulatory cascade in pancreatic cancer that may prove a promising new target for cancer intervention.