Rosiglitazone inhibits α4 nicotinic acetylcholine receptor expression in human lung carcinoma cells through peroxisome proliferator-activated receptor γ-independent signals

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 γ (PPARγ) 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 α4 nAChR, prompting us to explore the effects of rosiglitazone, a synthetic PPARγ ligand, on the expression of this receptor. Rosiglitazone inhibited the expression of α4 nAChR, but this effect was through a PPARγ-independent pathway, because GW9662, an antagonist of PPARγ, and the transfection of cells with PPARγ small interfering RNA failed to abolish the response. The inhibitory effect of rosiglitazone on α4 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 α4 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 upregulation was needed for rosiglitazone-induced inhibition of α4 nAChR. Thus, rosiglitazone inhibits α4 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 α4 nAChR. This process was also inhibited by rosiglitazone through similar pathways. Copyright © 2009 American Association for Cancer Research.