Novel link between prostaglandin E2 (PGE2) and cholinergic signaling in lung cancer: The role of c‐Jun in PGE2‐induced α7 nicotinic acetylcholine receptor expression and tumor cell proliferation

摘要

AbstractBackgroundCyclooxygenase-2-derived prostaglandin E₂ (PGE₂) stimulates tumor cell growth and progression. α7 nicotinic acetylcholine receptor (nAChR) is a major mediator of cholinergic signaling in tumor cells. In the present study, we investigated the mechanisms by which PGE₂ increases non-small cell lung cancer (NSCLC) proliferation via α7 nAChR induction.MethodsThe effects of PGE₂ on α7 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 PGE₂ on cell growth was determined by cell viability assay.ResultsWe found that PGE₂ induced α7 nAChR expression and its promoter activity in NSCLC cells. The stimulatory role of PGE₂ on cell proliferation was attenuated by α7 nAChR small interfering ribonucleic acids (siRNA) or acetylcholinesterase. PGE₂-induced α7 nAChR expression was blocked by an antagonist of the PGE₂ receptor subtype EP4 and by EP4 siRNA. Furthermore, PGE₂ enhanced α7 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 PGE₂ on α7 nAChR promoter activity and protein expression, and cell growth.ConclusionOur results demonstrate that PGE₂ promotes NSCLC cell growth through increased α7 nAChR expression. This effect is dependent on EP4-mediated activation of JNK, PI3K, and PKA signals that induce c-Jun protein expression and α7 nAChR gene promoter activity. Our findings unveil a novel link between prostanoids and cholinergic signaling.