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 ; (PPAR;) 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 A4 nAChR, prompting us to explore the effects of rosiglitazone, a synthetic PPAR; ligand, on the expression of this receptor. Rosiglitazone inhibited the expression of A4 nAChR, but this effect was through a PPAR;-independent pathway, because GW9662, an antagonist of PPAR;, and the transfection of cells with PPAR; small interfering RNA failed to abolish the response. The inhibitory effect of rosiglitazone on A4 nAChR expression was accompanied by phosphorylation of p38 mitogenactivated protein kinase and extracellular signal-regulated kinase 1/2 and down-regulation of Akt phosphorylation. These signals mediated the inhibitory effects of rosiglitazone on A4 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 A4 nAChR. Thus, rosiglitazone inhibits A4 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 A4 nAChR. This process was also inhibited by rosiglitazone through similar pathways.

Anticancer actions of PPARγ ligands: Current state and future perspectives in human lung cancer

“…Evidence to date suggests that these effects of nicotine and its derivatives are mediated by nicotinic acetylcholine receptors expressed on the surface of tumor cells, thereby contributing to tumor progression [69][70][71] . We recently found that rosiglitazone reduced nicotineinduced NSCLC cell growth through downregulation of α4 nAChR-dependent signals including ERK and p38 MAPK; this effect appeared to be PPARγ-independent [72] . We also found that nicotine increases PPARβ/δ gene expression through α7 nAChR-mediated activation of PI3K/mTOR signals.…”

Activated EGFR stimulates MUC1 expression in human uterine and pancreatic cancer cell lines

“…Our previous studies of rosiglitazone antagonism of progesterone‐stimulated MUC1 expression indicated that this response was partially PPARγ‐dependent [Wang et al, ]. Rosiglitazone mediated inhibition of nicotinic acetylcholine receptor (α4 nAChR) expression is PPARγ independent and involves the p38‐MAPK, ERK 1/2, and Akt pathways [Sun et al, ]. The TZD, troglitazone also inhibits the activation of the MAPK pathways in pancreatic cancer cells [Vitale et al, ].…”

Development of novel approach to diagnostic imaging of lung cancer with 18F-Nifene PET/CT using A/J Mice treated with NNK

“…Activation of nAChRs stimulates the growth of lung cancer cells, in part, through α 4 nAChR and suppresses apoptosis [23, 52–58], indicating that nicotine can act as a tumor promoter that facilitates the outgrowth of cells with genetic damage. In addition to a well-formulated etiologic role of tobacco nitrosamines in the genotoxic damage inducing lung cancer, recent studies have identified tobacco nitrosamines as high-affinity agonists of nAChRs that can upregulate cell growth [59].…”