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Nicotine Stimulates PPARβ/ Expression in Human Lung Carcinoma Cells through Activation of PI3K/mTOR and Suppression of AP-2

¹ Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Emory University School of Medicine; ² Atlanta Veterans Affairs Medical Center, Atlanta, Georgia and ³ Tianjin Medical University General Hospital, Tianjin Lung Cancer Institute, Tianjin Medical University, Tianjin, People's Republic of China

Requests for reprints: ShouWei Han, Division of Pulmonary, Allergy and Critical Care Medicine, Emory University School of Medicine, Whitehead Bioresearch Building, 615 Michael Street, Suite 205-M, Atlanta, GA 30322. Phone: 404-712-2661; Fax: 404-712-2151; E-mail: shan2{at}emory.edu.

Key Words: PPARβ/ • Nicotine • 7 nAChR • AP-2 • PI3K/mTOR • human lung carcinoma cells

We previously showed that nicotine stimulates non–small cell lung carcinoma (NSCLC) cell proliferation through nicotinic acetylcholine receptor (nAChR)–mediated signals. Activation of peroxisome proliferator–activated receptor β/ (PPARβ/) has also been shown to induce NSCLC cell growth. Here, we explore the potential link between nicotine and PPARβ/ and report that nicotine increases the expression of PPARβ/ protein; this effect was blocked by an 7 nAChR antagonist (-bungarotoxin), by 7 nAChR short interfering RNA, and by inhibitors of phosphatidylinositol 3-kinase (PI3K; wortmannin and LY294002) and mammalian target of rapamycin (mTOR; rapamycin). In contrast, this effect was enhanced by PUN282987, an 7 nAChR agonist. Silencing of PPARβ/ attenuated the stimulatory effect of nicotine on cell growth, which was overcome by transfection of an exogenous PPARβ/ expression vector. Of note, nicotine induced complex formation between 7 nAChR and PPARβ/ protein and increased PPARβ/ gene promoter activity through inhibition of AP-2 as shown by reduced AP-2 binding using electrophoretic gel mobility shift and chromatin immunoprecipitation assays. In addition, silencing of Sp1 attenuated the effect of nicotine on PPARβ/. Collectively, our results show that nicotine increases PPARβ/ gene expression through 7 nAChR–mediated activation of PI3K/mTOR signals that inhibit AP-2 protein expression and DNA binding activity to the PPARβ/ gene promoter. Sp1 seems to modulate this process. This study unveils a novel mechanism by which nicotine promotes human lung carcinoma cell growth. [Cancer Res 2009;69(16):6445–53]