Han ShouWei, Ritzenthaler Jeffrey D, Zheng Ying, Roman Jesse
Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Emory University School of Medicine, Whitehead Bioresearch Bldg., 615 Michael St., Suite 205-M, Atlanta, GA 30322, USA.
Am J Physiol Lung Cell Mol Physiol. 2008 Jun;294(6):L1238-49. doi: 10.1152/ajplung.00017.2008. Epub 2008 Apr 4.
Recent studies suggest that activation of peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) promotes cancer cell survival. We previously demonstrated that a selective PPARbeta/delta agonist, GW501516, stimulated human non-small cell lung carcinoma (NSCLC) cell growth. Here, we explore the mechanisms responsible for this effect. We show that GW501516 decreased phosphate and tensin homolog deleted on chromosome 10 (PTEN), a tumor suppressor known to decrease cell growth and induce apoptosis. Activation of PPARbeta/delta and phosphatidylinositol 3-kinase (PI3K)/Akt signaling was associated with inhibition of PTEN. GW501516 increased NF-kappaB DNA binding activity and p65 protein expression through activation of PPARbeta/delta and PI3K/Akt signals and enhanced the physical interactions between PPARbeta/delta and p65 protein. Conversely, inhibition of PI3K and silencing of p65 by small RNA interference (siRNA) blocked the effect of GW501516 on PTEN expression and on NSCLC cell proliferation. GW501516 also inhibited IKBalpha protein expression. Silencing of IKBalpha enhanced the effect of GW501516 on PTEN protein expression and on cell proliferation. It also augmented the GW501516-induced complex formation of PPARbeta/delta and p65 proteins. Overexpression of PTEN suppressed NSCLC cell growth and eliminated the effect of GW501516 on phosphorylation of Akt. Together, our observations suggest that GW501516 induces the proliferation of NSCLC cells by inhibiting the expression of PTEN through activation of PPARbeta/delta, which stimulates PI3K/Akt and NF-kappaB signaling. Overexpression of PTEN overcomes this effect and unveils PPARbeta/delta and PTEN as potential therapeutic targets in NSCLC.
近期研究表明，过氧化物酶体增殖物激活受体β/δ（PPARβ/δ）的激活可促进癌细胞存活。我们之前证明，一种选择性PPARβ/δ激动剂GW501516可刺激人非小细胞肺癌（NSCLC）细胞生长。在此，我们探究造成这种效应的机制。我们发现GW501516可降低第10号染色体上缺失的磷酸酶和张力蛋白同源物（PTEN），PTEN是一种已知可抑制细胞生长并诱导凋亡的肿瘤抑制因子。PPARβ/δ和磷脂酰肌醇3激酶（PI3K）/Akt信号的激活与PTEN的抑制相关。GW501516通过激活PPARβ/δ和PI3K/Akt信号增加核因子κB（NF-κB）的DNA结合活性及p65蛋白表达，并增强PPARβ/δ与p65蛋白之间的物理相互作用。相反，PI3K的抑制以及小RNA干扰（siRNA）介导的p65沉默可阻断GW501516对PTEN表达及NSCLC细胞增殖的影响。GW501516还可抑制IκBα蛋白表达。IκBα的沉默增强了GW501516对PTEN蛋白表达及细胞增殖的影响。它还增强了GW501516诱导的PPARβ/δ与p65蛋白复合物的形成。PTEN的过表达抑制NSCLC细胞生长，并消除GW501516对Akt磷酸化的影响。总之，我们的观察结果表明，GW501516通过激活PPARβ/δ抑制PTEN的表达，从而刺激PI3K/Akt和NF-κB信号，进而诱导NSCLC细胞增殖。PTEN的过表达可克服这种效应，并揭示PPARβ/δ和PTEN是NSCLC潜在的治疗靶点。
