Novel link between prostaglandin E 2 ( PGE 2 ) and cholinergic signaling in lung cancer: The role of c‐ J un in PGE 2 ‐induced α7 nicotinic acetylcholine receptor expression and tumor cell proliferation

Background Cyclooxygenase‐2‐derived prostaglandin E 2 ( PGE 2 ) 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 PGE 2 increases non‐small cell lung cancer ( NSCLC ) proliferation via α7 nAChR induction. Methods The effects of PGE 2 on α7 nAChR expression, promoter activity, and cell signaling pathways were detected by W estern 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. Results We found that PGE 2 induced α7 nAChR expression and its promoter activity in NSCLC cells. The stimulatory role of PGE 2 on cell proliferation was attenuated by α7 nAChR small interfering ribonucleic acids (si RNA ) or acetylcholinesterase. PGE 2 ‐induced α7 nAChR expression was blocked by an antagonist of the PGE 2 receptor subtype EP 4 and by EP 4 si RNA . Furthermore, PGE 2 enhanced α7 nAChR expression via activation of c‐ J un 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‐ J un diminished the effects of PGE 2 on α7 nAChR promoter activity and protein expression, and cell growth. Conclusion Our results demonstrate that PGE 2 promotes NSCLC cell growth through increased α7 nAChR expression. This effect is dependent on EP 4‐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.