Document Detail

Nicotine stimulates PPARbeta/delta expression in human lung carcinoma cells through activation of PI3K/mTOR and suppression of AP-2alpha.
MedLine Citation:
PMID:  19654299     Owner:  NLM     Status:  MEDLINE    
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 (PPARbeta/delta) has also been shown to induce NSCLC cell growth. Here, we explore the potential link between nicotine and PPARbeta/delta and report that nicotine increases the expression of PPARbeta/delta protein; this effect was blocked by an alpha7 nAChR antagonist (alpha-bungarotoxin), by alpha7 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 alpha7 nAChR agonist. Silencing of PPARbeta/delta attenuated the stimulatory effect of nicotine on cell growth, which was overcome by transfection of an exogenous PPARbeta/delta expression vector. Of note, nicotine induced complex formation between alpha7 nAChR and PPARbeta/delta protein and increased PPARbeta/delta gene promoter activity through inhibition of AP-2alpha as shown by reduced AP-2alpha binding using electrophoretic gel mobility shift and chromatin immunoprecipitation assays. In addition, silencing of Sp1 attenuated the effect of nicotine on PPARbeta/delta. Collectively, our results show that nicotine increases PPARbeta/delta gene expression through alpha7 nAChR-mediated activation of PI3K/mTOR signals that inhibit AP-2alpha protein expression and DNA binding activity to the PPARbeta/delta gene promoter. Sp1 seems to modulate this process. This study unveils a novel mechanism by which nicotine promotes human lung carcinoma cell growth.
XiaoJuan Sun; Jeffrey D Ritzenthaler; XiaoRong Zhong; Ying Zheng; Jesse Roman; ShouWei Han
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2009-08-04
Journal Detail:
Title:  Cancer research     Volume:  69     ISSN:  1538-7445     ISO Abbreviation:  Cancer Res.     Publication Date:  2009 Aug 
Date Detail:
Created Date:  2009-08-14     Completed Date:  2009-09-15     Revised Date:  2014-09-12    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  6445-53     Citation Subset:  IM    
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MeSH Terms
Bungarotoxins / pharmacology
Carcinoma, Non-Small-Cell Lung / genetics,  metabolism*
Cell Proliferation / drug effects
Cholinergic Agonists / pharmacology
Enzyme Activation / drug effects,  physiology
Gene Expression Regulation, Neoplastic
Lung Neoplasms / genetics,  metabolism*
Models, Biological
Nicotine / pharmacology*
PPAR delta / genetics,  metabolism*
PPAR-beta / genetics,  metabolism
Phosphatidylinositol 3-Kinases / metabolism*,  physiology
Promoter Regions, Genetic / drug effects
Protein Kinases / metabolism*,  physiology
Receptors, Nicotinic / physiology
TOR Serine-Threonine Kinases
Transcription Factor AP-2 / antagonists & inhibitors*,  metabolism
Tumor Cells, Cultured
Up-Regulation / drug effects
alpha7 Nicotinic Acetylcholine Receptor
Grant Support
CA116812/CA/NCI NIH HHS; CA123104/CA/NCI NIH HHS; K22 CA123104-01A2/CA/NCI NIH HHS; R01 CA116812/CA/NCI NIH HHS; R01 CA116812-01A2/CA/NCI NIH HHS; //Howard Hughes Medical Institute
Reg. No./Substance:
0/Bungarotoxins; 0/Cholinergic Agonists; 0/Chrna7 protein, human; 0/PPAR delta; 0/PPAR-beta; 0/Receptors, Nicotinic; 0/Transcription Factor AP-2; 0/alpha7 Nicotinic Acetylcholine Receptor; 54-11-5/Nicotine; EC 2.7.-/Protein Kinases; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC protein, human; EC Serine-Threonine Kinases

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