Novel link between prostaglandin E2 (PGE2) and cholinergic signaling in lung cancer: The role of c-Jun in PGE2-induced 7 nicotinic acetylcholine receptor expression and tumor cell proliferation

BackgroundCyclooxygenase-2-derived prostaglandin E-2 (PGE(2)) stimulates tumor cell growth and progression. 7 nicotinic acetylcholine receptor (nAChR) is a major mediator of cholinergic signaling in tumor cells. In the present study, we investigated the mechanisms by which PGE(2) increases non-small cell lung cancer (NSCLC) proliferation via 7 nAChR induction. MethodsThe effects of PGE(2) on 7 nAChR expression, promoter activity, and cell signaling pathways were detected by Western blot analysis, real time reverse transcriptase polymerase chain reaction, and transient transfection assay. The effect of PGE(2) on cell growth was determined by cell viability assay. ResultsWe found that PGE(2) induced 7 nAChR expression and its promoter activity in NSCLC cells. The stimulatory role of PGE(2) on cell proliferation was attenuated by 7 nAChR small interfering ribonucleic acids (siRNA) or acetylcholinesterase. PGE(2)-induced 7 nAChR expression was blocked by an antagonist of the PGE(2) receptor subtype EP4 and by EP4 siRNA. Furthermore, PGE(2) enhanced 7 nAChR expression via activation of c-Jun N-terminal kinase (JNK), phosphatidylinositol 3-kinase (PI3-K), and protein kinase A (PKA) pathways followed by increased c-Jun expression, a critical transcription factor. Blockade of c-Jun diminished the effects of PGE(2) on 7 nAChR promoter activity and protein expression, and cell growth. ConclusionOur results demonstrate that PGE(2) promotes NSCLC cell growth through increased 7 nAChR expression. This effect is dependent on EP4-mediated activation of JNK, PI3K, and PKA signals that induce c-Jun protein expression and 7 nAChR gene promoter activity. Our findings unveil a novel link between prostanoids and cholinergic signaling.