Fan Yu, Wang Ke
Department of Radiotherapy, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, P.R. China 610041.
Department of Respiratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province, P.R. China 610041.
Oncotarget. 2017 May 19;8(44):75854-75863. doi: 10.18632/oncotarget.18023. eCollection 2017 Sep 29.
It was demonstrated that nicotine increased non-small cell lung cancer cell proliferation through nicotinic acetylcholine receptor -mediated signals. However, the detailed mechanism remains incompletely understood. We evaluated whether nicotine increased EP4 receptor expression in lung carcinoma cells by activating on AP-2α.
The non-small cell lung cancer cells of A549 and H1838 were cultured and treated with EP4 inhibitor AH23848, also with EP4 and control siRNAs. The extracellular signal-regulated kinases inhibitor PD98059, the p38 mitogen-activated protein kinase inhibitor SB239063, the α7 nicotinic acetylcholine receptor inhibitor α-bungarotoxin, the α4 nicotinic acetylcholine receptor inhibitor dihydro-β-erythroidine, the PI3K inhibitor wortmannin, the PKC inhibitor calphostin C, and the PKA inhibitor H89 have been used to evaluate the effects on proliferations. It indicates that nicotine increases EP4 expression through α7 nicotinic acetylcholine receptor-dependent activations of PI3-K, JNK and PKC pathways that leads to reduction of AP-2α-DNA binding. This, together with the elevated secretion of PGE, further enhances the tumor promoting effects of nicotine. These studies suggest a novel molecular mechanism by which nicotine increases non-small cell lung cancer cell proliferation.
已证明尼古丁通过烟碱型乙酰胆碱受体介导的信号增加非小细胞肺癌细胞的增殖。然而，详细机制仍未完全了解。我们评估了尼古丁是否通过激活AP-2α来增加肺癌细胞中EP4受体的表达。
培养A549和H1838非小细胞肺癌细胞，并用EP4抑制剂AH23848以及EP4和对照小干扰RNA进行处理。使用细胞外信号调节激酶抑制剂PD98059、p38丝裂原活化蛋白激酶抑制剂SB239063、α7烟碱型乙酰胆碱受体抑制剂α-银环蛇毒素、α4烟碱型乙酰胆碱受体抑制剂二氢-β-刺桐啶、PI3K抑制剂渥曼青霉素、PKC抑制剂钙泊三醇C和PKA抑制剂H89来评估对增殖的影响。结果表明，尼古丁通过PI3-K、JNK和PKC途径的α7烟碱型乙酰胆碱受体依赖性激活增加EP4表达，这导致AP-2α与DNA结合减少。这与PGE分泌增加一起，进一步增强了尼古丁的促肿瘤作用。这些研究提示了尼古丁增加非小细胞肺癌细胞增殖的一种新的分子机制。
