Nicotine induces EP4 receptor expression in lung carcinoma cells by acting on AP-2α: The intersection between cholinergic and prostanoid signaling

Abstract

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. Methods: 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 PGE₂, 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.