Rosiglitazone inhibits alpha4 nicotinic acetylcholine receptor expression in human lung carcinoma cells through peroxisome proliferator-activated receptor gamma-independent signals
Authors: Jesse Roman
Jeffrey D Ritzenthaler
ShouWei Han
Xiaojuan Sun
Ying Zheng
Journal: Molecular Cancer Therapeutics (2009)
Discipline: CLINICAL MEDICINE
Keywords: nicotine; non-small cell lung carcinoma; NSCLC; nicotinic acetylcholine receptor; PPARgamma
Affiliations: Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Emory University School of Medicine, Whitehead Bioresearch Building, 615 Michael Street, Suite 205-M, Atlanta, GA 30322, USA.

Abstract:  We and others have shown previously that nicotine, a major component of tobacco, stimulates non-small cell lung carcinoma (NSCLC) proliferation through nicotinic acetylcholine receptor (nAChR)-mediated signals. Activation of peroxisome proliferator-activated receptor gamma (PPARgamma) has been shown to inhibit NSCLC cell growth, but the exact mechanisms responsible for this effect remain incompletely defined. Herein, we show that nicotine induces NSCLC cell proliferation in part through alpha4 nAChR, prompting us to explore the effects of rosiglitazone, a synthetic PPARgamma ligand, on the expression of this receptor. Rosiglitazone inhibited the expression of alpha4 nAChR, but this effect was through a PPARgamma-independent pathway, because GW9662, an antagonist of PPARgamma, and the transfection of cells with PPARgamma small interfering RNA failed to abolish the response. The inhibitory effect of rosiglitazone on alpha4 nAChR expression was accompanied by phosphorylation of p38 mitogen-activated protein kinase and extracellular signal-regulated kinase 1/2 and down-regulation of Akt phosphorylation. These signals mediated the inhibitory effects of rosiglitazone on alpha4 nAChR expression because chemical inhibitors prevented the effect. Rosiglitazone was also found to stimulate p53, a tumor suppressor known to mediate some of the effects of nicotine. Interestingly, p53 up-regulation was needed for rosiglitazone-induced inhibition of alpha4 nAChR. Thus, rosiglitazone inhibits alpha4 nAChR expression in NSCLC cells through activation of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase, which triggers induction of p53. Finally, like others, we found that nicotine stimulated the expression of alpha4 nAChR. This process was also inhibited by rosiglitazone through similar pathways. 

Retracted: No

PubPeer comments:
 image duplication ![file] Disclaimer: These potential image duplications have been detected automatically using ImageTwin http: dx.doi.org 10.1145 3019612.3019875 Although results have been curated, the automatic algorithm may have generated false positive results and cannot take into account all scientific explanations for apparent duplications like stripped and reprobed blots, time series, serial sections and reused controls. , 
 #1 I agree that these two images appear to overlap, but wonder if they may not be sequential sections. *** ![file] , 
 #2 Should dKO and ApoE- - co-occur so precisely? Would the fine structure of tissue differ slightly, even between sequential slices? ![file] ,