4.8 Article

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

Journal

CANCER RESEARCH
Volume 69, Issue 16, Pages 6445-6453

Publisher

AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-09-1001

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Funding

  1. NIH [CA123104, CA116812]

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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 beta/delta (PPAR beta/delta) has also been shown to induce NSCLC cell growth. Here, we explore the potential link between nicotine and PPAR beta/delta and report that nicotine increases the expression of PPAR beta/delta protein; this effect was blocked by an alpha 7 nAChR antagonist (alpha-bungarotoxin), by alpha 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 alpha 7 nAChR agonist. Silencing of PPAR beta/delta attenuated the stimulatory effect of nicotine on cell growth, which was overcome by transfection of an exogenous PPAR beta/delta expression vector. Of note, nicotine induced complex formation between alpha 7 nAChR and PPAR beta/delta protein and increased PPAR beta/delta gene promoter activity through inhibition of AP-2 alpha as shown by reduced AP-2 alpha binding using electrophoretic gel mobility shift and chromatin immunoprecipitation assays. In addition, silencing of Sp1 attenuated the effect of nicotine on PPAR beta/delta. Collectively, our results show that nicotine increases PPAR beta/delta gene expression through alpha 7 nAChR-mediated activation of PI3K/mTOR signals that inhibit AP-2 alpha protein expression and DNA binding activity to the PPAR beta/delta 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]

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