title: GW1929 inhibits α7 nAChR expression through PPARγ-independent activation of p38 MAPK and inactivation of PI3-K/mTOR: The role of Egr-1.
abstract: Studies demonstrated that peroxisome proliferator-activated receptor gamma (PPARγ) ligands reduce nicotine-induced non small cell lung carcinoma (NSCLC) cell growth through inhibition of nicotinic acetylcholine receptor (nAChR) mediated signaling pathways. However, the mechanisms by which PPARγ ligands inhibited nAChR expression remain elucidated. Here, we show that GW1929, a synthetic PPARγ ligand, not only inhibited but also antagonized the stimulatory effect of acetylcholine on NSCLC cell proliferation. Interestingly, GW1929 inhibited α7 nAChR expression, which was not blocked by GW9662, an antagonist of PPARγ, or by PPARγ siRNA, but was abrogated by the p38 MPAK inhibitor SB239063. GW1929 reduced the promoter activity of α7 nAChR and induced early growth response-1 (Egr-1) protein expression, which was overcame by SB239063, but enhanced by inhibitors of PI3-K and mTOR. Silencing of Egr-1 blocked, while overexpression of Egr-1 enhanced, the effect of GW1929 on α7 nAChR expression and promoter activity. Finally, GW1929 induced Egr-1 bound to specific DNA areas in the α7 nAChR gene promoter. Collectively, these results demonstrate that GW1929 not only inhibits but also antagonizes Ach-induced NSCLC cell growth by inhibition of α7 nAChR expression through PPARγ-independent signals that are associated with activation of p38 MPAK and inactivation of PI3-K/mTOR, followed by inducing Egr-1 protein and Egr-1 binding activity in the α7 nAChR gene promoter. By downregulation of the α7 nAchR, GW1929 blocks cholinergic signaling and inhibits NSCLC cell growth.
authors.affiliation: Laboratory of Tumor Molecular Biology and Targeted Therapies, University of Guangzhou Traditional Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong Province 510006, China. Electronic address: swhan2010@live.com.
authors.forename: Swei Sunny
authors.initials: SS
authors.lastname: Hahn
authors.affiliation: Laboratory of Tumor Molecular Biology and Targeted Therapies, University of Guangzhou Traditional Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong Province 510006, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Tang
authors.affiliation: Laboratory of Tumor Molecular Biology and Targeted Therapies, University of Guangzhou Traditional Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong Province 510006, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Zheng
authors.affiliation: Laboratory of Tumor Molecular Biology and Targeted Therapies, University of Guangzhou Traditional Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong Province 510006, China.
authors.forename: Shunyu
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Laboratory of Tumor Molecular Biology and Targeted Therapies, University of Guangzhou Traditional Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong Province 510006, China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Wu
mesh_terms: D000813:Anilides / Q000494:pharmacology; D001577:Benzophenones / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D051766:Early Growth Response Protein 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000813:Anilides; D001577:Benzophenones; D051766:Early Growth Response Protein 1; D047495:PPAR gamma; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D034741:RNA, Small Interfering; D058570:TOR Serine-Threonine Kinases; D014443:Tyrosine; D064569:alpha7 Nicotinic Acetylcholine Receptor; D048051:p38 Mitogen-Activated Protein Kinases; C457499:2-chloro-5-nitrobenzanilide; C497325:EGR1 protein, human; C546842:MTOR protein, human; C120099:GW 1929
keywords: Egr-1; GW1929; Human lung adenocarcinoma cells; PPARγ; p38 MPAK; α7nAchR