Studies demonstrated that peroxisome proliferator-activated receptor gamma (PPAR gamma) 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 PPARy ligands inhibited nAChR expression remain elucidated. Here, we show that GW1929, a synthetic PPAR gamma ligand, not only inhibited but also antagonized the stimulatory effect of acetylcholine on NSCLC cell proliferation. Interestingly, GW1929 inhibited alpha 7 nAChR expression, which was not blocked by GW9662, an antagonist of PPAR gamma, or by PPAR gamma siRNA, but was abrogated by the p38 MPAK inhibitor SB239063. GW1929 reduced the promoter activity of alpha 7 nAChR and induced early growth response-1 (Egr-1) protein expression, which was overcame by SB239063, but enhanced by inhibitors of P13-K and mTOR Silencing of Egr-1 blocked, while overexpression of Egr-1 enhanced, the effect of GW1929 on alpha 7 nAChR expression and promoter activity. Finally, GW1929 induced Egr-1 bound to specific DNA areas in the alpha 7 nAChR gene promoter. Collectively, these results demonstrate that GWI 929 not only inhibits but also antagonizes Ach-induced NSCLC cell growth by inhibition of alpha 7 nAChR expression through PPAR gamma-independent signals that are associated with activation of p38 MPAK and inactivation of P13-K/mTOR, followed by inducing Egr-1 protein and Egr-1 binding activity in the alpha 7 nAChR gene promoter. By down-regulation of the alpha 7 nAchlt, GW1929 blocks cholinergic signaling and inhibits NSCLC cell growth. (C) 2014 Elsevier Inc. All rights reserved.