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首页> 外文期刊>Journal of Pathology: Journal of the Pathological Society of Great Britain and Ireland >Nicotinic receptor-associated modulation of stimulatory and inhibitory neurotransmitters in NNK-induced adenocarcinoma of the lungs and pancreas.
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Nicotinic receptor-associated modulation of stimulatory and inhibitory neurotransmitters in NNK-induced adenocarcinoma of the lungs and pancreas.

机译：NNK诱导的肺和胰腺腺癌中刺激性和抑制性神经递质的烟碱受体相关调节。

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Small airway-derived pulmonary adenocarcinoma (PAC) and pancreatic ductal adenocarcinoma (PDAC) are among the most common human cancers and smoking is a risk factor for both. Emerging research has identified cAMP signalling stimulated by the stress neurotransmitters adrenaline and noradrenaline as an important stimulator of adenocarcinomas, including PAC and PDAC. The nicotine-derived nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a potent mutagen and the most powerful tobacco carcinogen. NNK is also an agonist for nicotinic acetylcholine receptors (nAChRs). Using hamster models of NNK-induced PAC and PDAC, we have tested the hypothesis that in analogy to chronic effects of nicotine in the brain, NNK may modulate the alpha(7)- and alpha(4)beta(2)nAChRs, causing an increase in stress neurotransmitters and a decrease in the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). Immunoassays showed a significant increase in serum adrenalineoradrenaline and increased intracellular cAMP in the cellular fraction of blood of NNK-treated hamsters. Western blots on microdissected control small airway epithelia, alveolar epithelia, pancreatic islet and pancreatic duct epithelia, and from NNK-induced PACs and PDACs showed that the GABA-synthesizing enzyme glutamate decarboxylase 65 (GAD65) and GABA were suppressed in NNK-induced PACs and PDACs. In contrast, protein expression of the alpha(7)nAChR, alpha(4)nAChR as well as p-CREB and p-ERK1/2 were up-regulated. These findings suggest that NNK-induced alterations in regulatory nAChRs may contribute to the development of smoking-associated PAC and PDAC by disturbing the balance between cancer-stimulating and -inhibiting neurotransmitters.
机译：小型气道源性肺腺癌（PAC）和胰腺导管腺癌（PDAC）是最常见的人类癌症，吸烟是两者的危险因素。新兴的研究已经确定，应激神经递质肾上腺素和去甲肾上腺素刺激的cAMP信号传导是包括PAC和PDAC在内的腺癌的重要刺激物。尼古丁衍生的亚硝胺4-（甲基亚硝胺基）-1-（3-吡啶基）-1-丁酮（NNK）是有效的诱变剂，也是最强大的烟草致癌物。 NNK也是烟碱乙酰胆碱受体（nAChRs）的激动剂。使用NNK诱导的PAC和PDAC的仓鼠模型，我们测试了以下假设：类似于大脑中尼古丁的慢性作用，NNK可能会调节alpha（7）-和alpha（4）beta（2）nAChRs，从而导致应激神经递质增加，抑制性神经递质γ-氨基丁酸（GABA）减少。免疫测定显示，在经NNK处理的仓鼠的血液中，肾上腺素/去甲肾上腺素/血清肾上腺素/肾上腺素显着增加，细胞内cAMP升高。在微解剖的对照小气道上皮细胞，肺泡上皮细胞，胰岛和胰管上皮细胞上以及从NNK诱导的PAC和PDAC中进行的Western印迹显示NNK诱导的PAC和PDAC。相反，α（7）nAChR，α（4）nAChR以及p-CREB和p-ERK1 / 2的蛋白质表达被上调。这些发现表明，NNK诱导的调节性nAChRs的改变可能通过干扰刺激癌症的神经递质和抑制神经递质的平衡来促进与吸烟相关的PAC和PDAC的发展。

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