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. Issue 4 (14th January 2015)

• Record Type: Journal Article
• Authors: Zhong, XiaoRong; Fan, Yu; Ritzenthaler, Jeffrey D.; Zhang, WenJing; Wang, Ke; Zhou, QingHua; Roman, Jesse
• Is Part Of: Thoracic cancer. Volume 6:Issue 4(2015)
• Page Start: 488
• Page End: 500
• Publication Date: 2015-01-14
• Subjects: Chest -- Cancer -- Periodicals; Chest -- Cancer -- Treatment -- Periodicals; Chest -- Surgery -- Periodicals; 616.99494005
• DOI: 10.1111/1759-7714.12219
• Languages: English
• ISSNs: 1759-7706

Abstract

<abstract abstract-type="main"> <title>Abstract</title> <sec id="tca12219-sec-0001" sec-type="section"> <title>Background</title> <p>Cyclooxygenase‐2‐derived prostaglandin E<sub>2</sub> (PGE<sub>2</sub>) 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<sub>2</sub> increases non‐small cell lung cancer (NSCLC) proliferation via α7 nAChR induction.</p> </sec> <sec id="tca12219-sec-0002" sec-type="section"> <title>Methods</title> <p>The effects of PGE<sub>2</sub> 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 PGE<sub>2</sub> on cell growth was determined by cell viability assay.</p> </sec> <sec id="tca12219-sec-0003" sec-type="section"> <title>Results</title> <p>We found that PGE<sub>2</sub> induced α7 nAChR expression and its promoter activity in NSCLC cells. The stimulatory role of PGE<sub>2</sub> on cell proliferation was attenuated by α7 nAChR small interfering ribonucleic acids (siRNA) or acetylcholinesterase. PGE<sub>2</sub>‐induced α7 nAChR expression was blocked by an antagonist of the PGE<sub>2</sub> receptor subtype EP4 and by EP4 siRNA. Furthermore, PGE<sub>2</sub> 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 PGE<sub>2</sub> on α7 nAChR promoter activity and protein expression, and cell growth.</p> </sec> <sec id="tca12219-sec-0004" sec-type="section"> <title>Conclusion</title> <p>Our results demonstrate that PGE<sub>2</sub> 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.</p> </sec> </abstract>