Nicotine stimulates PPARbeta/delta expression in human lung carcinoma cells through activation of PI3K/mTOR and suppression of AP-2alpha.
Nicotine stimulates PPARbeta/delta expression in human lung carcinoma cells through activation of PI3K/mTOR and suppression of AP-2alpha.
复制标题
DOI：
10.1158/0008-5472.can-09-1001
复制
发表时间：
2009-08-15
期刊：
影响因子：
11.2
通讯作者：
Han S
中科院分区：
文献类型：
--
作者：
Sun X;Ritzenthaler JD;Zhong X;Zheng Y;Roman J;Han S
我们先前证明尼古丁通过烟碱乙酰胆碱受体（nAChR）介导的信号刺激非小细胞肺癌（NSCLC）细胞增殖。过氧化物酶体增殖物激活受体β/δ（PPARβ/δ）的激活也可诱导NSCLC细胞生长。在这里，我们探索了尼古丁与PPARβ/δ之间的潜在联系，并报告尼古丁增加了PPARβ/δ蛋白的表达;这种作用被α7 nAChR拮抗剂（α-银环蛇毒素）、α7 nAChR siRNA、PI 3-K抑制剂（Wortmannin和LY 294002）和mTOR（雷帕霉素）阻断。相反，这种作用被α7 nAChR激动剂PUN 282987增强。通过转染外源性PPARβ/δ表达载体，抑制PPARβ/δ的表达，减弱了尼古丁对细胞生长的刺激作用。值得注意的是，尼古丁诱导α7 nAChR和PPARβ/δ蛋白之间形成复合物，并通过抑制AP-2α增加PPARβ/δ基因启动子活性，如电泳凝胶迁移率变化和ChIP试验中AP-2α结合减少所示。此外，Sp1的沉默减弱了尼古丁对PPARβ/δ的影响。总的来说，我们的结果表明，尼古丁通过α7 nAChR介导的PI 3-K/mTOR信号激活增加了PPARβ/δ基因表达，PI 3-K/mTOR信号抑制了AP-2α蛋白表达和DNA与PPARβ/δ基因启动子的结合活性。Sp1似乎调节了这一过程。这项研究揭示了尼古丁促进人肺癌细胞生长的新机制。
We previously demonstrated 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 (PPARβ/δ) has also been shown to induce NSCLC cell growth. Here, we explore the potential link between nicotine and PPARβ/δ and report that nicotine increases the expression of PPARβ/δ protein; this effect was blocked by an α7 nAChR antagonist (α-bungarotoxin), by α7 nAChR siRNA, and by inhibitors of PI3-K (Wortmannin and LY294002), and mTOR (rapamycin). In contrast, this effect was enhanced by PUN282987, an α7 nAChR agonist. Silencing of PPARβ/δ attenuated the stimulatory effect of nicotine on cell growth which was overcome by transfection of an exogenous PPARβ/δ expression vector. Of note, nicotine induced complex formation between α7 nAChR and PPARβ/δ protein and increased PPARβ/δ gene promoter activity through inhibition of AP-2α as demonstrated by reduced AP-2α binding using electrophoretic gel mobility shift and ChIP assays. In addition, silencing of Sp1 attenuated the effect of nicotine on PPARβ/δ. Collectively, our results demonstrate that nicotine increases PPARβ/δ gene expression through α7 nAChR-mediated activation of PI3-K/mTOR signals that inhibit AP-2α protein expression and DNA binding activity to the PPARβ/δ gene promoter. Sp1 appears to modulate this process. This study unveils a novel mechanism by which nicotine promotes human lung carcinoma cell growth.