文章：

尼古丁通过乙酰胆碱和/或β-肾上腺素受体依赖途径调控人肺癌细胞中血管内皮生长因子信号传导

Regulation of Vascular Endothelial Growth Factor Signaling by Nicotine in a Manner Dependent on Acetylcholine-and/or β-Adrenergic-Receptors in Human Lung Cancer Cells

原文发布日期：21 November 2023

DOI: 10.3390/cancers15235500

类型: Article

开放获取: 是

英文摘要：

In addition to binding to nicotinic acetylcholine receptors (nAChRs), nicotine is known to regulate the β-adrenergic receptors (β-ARs) promoting oncogenic signaling. Using A549 (p53 wild-type) and H1299 (p53-null) lung cancer cells, we show that nicotine treatment led to: increased adrenaline/noradrenaline levels, an effect blocked by treatment with the α7nAChR inhibitor (α-BTX) but not by the β-blocker (propranolol) or the α4β2nAChR antagonist (DhβE); decreased GABA levels in A549 and H1299 cell media, an effect blocked by treatment with DhβE; increased VEGF levels and PI3K/AKT activities, an effect diminished by cell co-treatment with α-BTX, propranolol, and/or DhβE; and inhibited p53 activity in A549 cells, that was reversed, upon cell co-treatment with α-BTX, propranolol, and/or DhβE or by VEGF immunodepletion. VEGF levels increased upon cell treatment with nicotine, adrenaline/noradrenaline, and decreased with GABA treatment. On the other hand, the p53 activity decreased in A549 cells treated with nicotine, adrenaline/noradrenaline and increased upon cell incubation with GABA. Knockdown of p53 led to increased VEGF levels in the media of A549 cells. The addition of anti-VEGF antibodies to A549 and H1299 cells decreased cell viability and increased apoptosis; blocked the activities of PI3K, AKT, and NFκB in the absence or presence of nicotine; and resulted in increased p53 activation in A549 cells. We conclude that VEGF can be upregulated via α7nAChR and/or β-ARs and downregulated via GABA and/or p53 in response to the nicotine treatment of NSCLC cells.

摘要翻译： 

除与烟碱型乙酰胆碱受体结合外，尼古丁还能调控β-肾上腺素受体从而促进致癌信号传导。通过使用A549（p53野生型）和H1299（p53缺失型）肺癌细胞，我们发现尼古丁处理可导致：肾上腺素/去甲肾上腺素水平升高，该效应可被α7nAChR抑制剂（α-BTX）阻断，但不受β受体阻滞剂（普萘洛尔）或α4β2nAChR拮抗剂（DhβE）影响；A549和H1299细胞培养基中GABA水平降低，该效应可被DhβE阻断；VEGF水平及PI3K/AKT活性升高，该效应在细胞联合使用α-BTX、普萘洛尔和/或DhβE处理后减弱；以及A549细胞中p53活性受抑制，该现象在细胞联合使用α-BTX、普萘洛尔和/或DhβE处理或通过VEGF免疫清除后得以逆转。细胞经尼古丁、肾上腺素/去甲肾上腺素处理后VEGF水平升高，而GABA处理可降低其水平。另一方面，经尼古丁、肾上腺素/去甲肾上腺素处理的A549细胞中p53活性降低，而GABA孵育后其活性升高。敲低p53可导致A549细胞培养基中VEGF水平升高。向A549和H1299细胞添加抗VEGF抗体可降低细胞活力并增加细胞凋亡；在尼古丁存在或缺失条件下均能阻断PI3K、AKT和NFκB活性；并增强A549细胞中p53的激活。我们得出结论：在非小细胞肺癌细胞中，尼古丁处理可通过α7nAChR和/或β-ARs上调VEGF表达，同时通过GABA和/或p53途径下调其表达。

原文链接：

Regulation of Vascular Endothelial Growth Factor Signaling by Nicotine in a Manner Dependent on Acetylcholine-and/or β-Adrenergic-Receptors in Human Lung Cancer Cells