Rosiglitazone inhibits alpha4 nicotinic acetylcholine receptor expression in human lung carcinoma cells through peroxisome proliferator-activated receptor gamma-independent signals.
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.
Sun
Xiaojuan
X
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.
Ritzenthaler
Jeffrey D
JD
Zheng
Ying
Y
Roman
Jesse
J
Han
ShouWei
S
D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D047495:PPAR gamma / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000378:metabolism*; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000187:drug effects; D045162:Thiazolidinediones / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D048049:Extracellular Signal-Regulated MAP Kinases; D047495:PPAR gamma; D011978:Receptors, Nicotinic; D000077154:Rosiglitazone; D045162:Thiazolidinediones; D016159:Tumor Suppressor Protein p53; D048051:p38 Mitogen-Activated Protein Kinases