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Nicotine stimulates PPARbeta/delta expression in human lung carcinoma cells through activation of PI3K/mTOR and suppression of AP-2alpha.

ABSTRACT: 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.

SUBMITTER: Sun X

PROVIDER: S-EPMC2745317 | biostudies-literature | 2009 Aug

REPOSITORIES: biostudies-literature

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Nicotine stimulates PPARbeta/delta expression in human lung carcinoma cells through activation of PI3K/mTOR and suppression of AP-2alpha.

Sun XiaoJuan X Ritzenthaler Jeffrey D JD Zhong XiaoRong X Zheng Ying Y Roman Jesse J Han ShouWei S

Cancer research 20090804 16

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 anta ...[more]

PMID: 19654299

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Project description:BackgroundPsoriasis is one of the most frequent skin diseases world-wide. The disease impacts enormously on affected patients and poses a huge financial burden on health care providers. Several lines of evidence suggest that the nuclear hormone receptor peroxisome proliferator activator (PPAR) beta/delta, known to regulate epithelial differentiation and wound healing, contributes to psoriasis pathogenesis. It is unclear, however, whether activation of PPARbeta/delta is sufficient to trigger psoriasis-like changes in vivo.Methodology/principal findingsUsing immunohistochemistry, we define the distribution of PPARbeta/delta in the skin lesions of psoriasis. By expression profiling, we confirm that PPARbeta/delta is overexpressed in the vast majority of psoriasis patients. We further establish a transgenic model allowing inducible activation of PPARbeta/delta in murine epidermis mimicking its distribution in psoriasis lesions. Upon activation of PPARbeta/delta, transgenic mice sustain an inflammatory skin disease strikingly similar to psoriasis, featuring hyperproliferation of keratinocytes, dendritic cell accumulation, and endothelial activation. Development of this phenotype requires the activation of the Th17 subset of T cells, shown previously to be central to psoriasis. Moreover, gene dysregulation in the transgenic mice is highly similar to that in psoriasis. Key transcriptional programs activated in psoriasis, including IL1-related signalling and cholesterol biosynthesis, are replicated in the mouse model, suggesting that PPARbeta/delta regulates these transcriptional changes in psoriasis. Finally, we identify phosphorylation of STAT3 as a novel pathway activated by PPARbeta/delta and show that inhibition of STAT3 phosphorylation blocks disease development.ConclusionsActivation of PPARbeta/delta in the epidermis is sufficient to trigger inflammatory changes, immune activation, and signalling, and gene dysregulation characteristic of psoriasis.

Project description:Peroxisome proliferator-activated receptor (PPAR) beta/delta-null mice exhibit exacerbated hepatotoxicity in response to administration of carbon tetrachloride (CCl(4)). To determine whether ligand activation of the receptor protects against chemical toxicity in the liver, wild-type and PPARbeta/delta-null mice were administered CCl(4) with or without coadministration of the highly specific PPARbeta/delta ligand GW0742. Biomarkers of liver toxicity, including serum alanine aminotransferase (ALT) and hepatic tumor necrosis factor (TNF) alpha mRNA, were significantly higher in CCl(4)-treated PPARbeta/delta-null mice compared to wild-type mice. Hepatic expression of TNF-like weak inducer of apoptosis receptor (TWEAKr) and S100 calcium-binding protein A6 (S100A6/calcyclin), genes involved in nuclear factor kappa B signaling, was higher in the CCl(4)-treated PPARbeta/delta-null mice compared to wild-type mice. GW0742 treatment resulted in reduced serum ALT concentration and lower expression of CCl(4)-induced TNF-alpha, S100A6, monocyte chemoattractant protein-1 (MCP1), and TWEAKr in wild-type mice, and these effects were not observed in PPARbeta/delta-null mice. Expression of TNF-alpha was higher in PPARbeta/delta-null primary hepatocytes in response to interleukin-1beta treatment compared to wild-type hepatocytes, but GW0742 did not significantly modulate TNF-alpha expression in hepatocytes from either genotype. While PPARbeta/delta-null hepatic stellate exhibited higher rates of proliferation compared to wild-type cells, GW0742 did not affect alpha-smooth muscle actin expression in these cells. Combined, these findings demonstrate that ligand activation of PPARbeta/delta protects against chemically induced hepatotoxicity by downregulating expression of proinflammatory genes. Hepatocytes and hepatic stellate cells do not appear to directly mediate the inhibitory effects of ligand activation of PPARbeta/delta in liver, suggesting the involvement of paracrine and autocrine events mediated by hepatic cells.

Dataset Information

Nicotine stimulates PPARbeta/delta expression in human lung carcinoma cells through activation of PI3K/mTOR and suppression of AP-2alpha.

Publications

Nicotine stimulates PPARbeta/delta expression in human lung carcinoma cells through activation of PI3K/mTOR and suppression of AP-2alpha.

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