Peroxisome proliferator-activated receptor-gamma activation inhibits tumor metastasis by antagonizing Smad3-mediated epithelial-mesenchymal transition.
Peroxisome proliferator-activated receptor-gamma activation inhibits tumor metastasis by antagonizing Smad3-mediated epithelial-mesenchymal transition.
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DOI：
10.1158/1535-7163.mct-10-0570
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发表时间：
2010-12
影响因子：
5.7
通讯作者：
Keshamouni VG
中科院分区：
文献类型：
--
作者：
Reka AK;Kurapati H;Narala VR;Bommer G;Chen J;Standiford TJ;Keshamouni VG
上皮-间质转化（EMT）被证明赋予肿瘤细胞转移所必需的能力，包括迁移表型、侵袭性、抗凋亡、逃避免疫监视和肿瘤干细胞特性。因此，抑制EMT可能是抑制肿瘤转移的重要治疗策略。在这里，我们证明了过氧化物酶体增殖物激活受体（PPAR）-γ的激活抑制TGF-β诱导的肺癌细胞EMT，并通过拮抗Smad 3功能防止转移。通过合成配体（Troglitazone和罗格列酮）或通过组成型活性形式的PPAR-γ激活可防止TGF-β诱导的E-钙粘蛋白表达丧失，并抑制间充质标志物（波形蛋白、N-钙粘蛋白、纤连蛋白）和MMP的诱导。因此，激活PPAR-γ也可抑制EMT诱导的肺癌细胞迁移和侵袭。此外，通过siRNA介导的PPAR-γ敲低减弱了PPAR-γ配体的作用，表明配体诱导的应答是PPAR-γ依赖性的。通过siRNA选择性地敲低Smad 2和Smad 3，证实TGF-β诱导的EMT在肺癌细胞中是Smad 3依赖性的。激活PPAR-γ抑制TGF-β诱导的Smad转录活性，但对Smads的磷酸化或核转位没有影响。持续的PPAR-γ激活阻止了TGF-β诱导的E-钙粘蛋白启动子的转录抑制，并抑制了N-钙粘蛋白启动子的转录激活。最后，在Scid-Beige小鼠中，用曲格列酮治疗小鼠或敲低肿瘤细胞中的Smad 3均显著抑制TGF-β诱导的实验转移。同时，与低毒性的PPAR-γ配体，我们的数据表明，这些配体可以作为潜在的治疗剂，以抑制转移。
Epithelial-mesenchymal transition (EMT) was shown to confer tumor cells with abilities essential for metastasis, including migratory phenotype, invasiveness, and resistance to apoptosis, evading immune surveillance and tumor stem cell traits. Therefore, inhibition of EMT can be an important therapeutic strategy to inhibit tumor metastasis. Here we demonstrate that activation of peroxisome proliferator activated receptor (PPAR) -γ inhibits TGF-β-induced EMT in lung cancer cells and prevents metastasis by antagonizing Smad3 function. Activation of PPAR-γ by synthetic ligands (Troglitazone and Rosiglitazone) or by a constitutively-active form of PPAR-γ prevents TGF-β-induced loss of E-cadherin expression and inhibited the induction of mesenchymal markers (vimentin, N-cadherin, fibronectin) and MMPs. Consistently, activation of PPAR-γ also inhibited EMT-induced migration and invasion of lung cancer cells. Furthermore, effects of PPAR-γ ligands were attenuated by siRNA mediated knockdown of PPAR-γ, indicating that the ligand induced responses are PPAR-γ dependent. Selective knockdown of Smad2 and Smad3 by siRNA demonstrated that TGF-β-induced EMT is Smad3 dependent in lung cancer cells. Activation of PPAR-γ inhibits TGF-β-induced Smad transcriptional activity but had no effect on the phosphorylation or nuclear translocation of Smads. Consistently PPAR-γ activation prevented TGF-ß-induced transcriptional repression of E-cadherin promoter and inhibited transcriptional activation of N-cadherin promoter. Finally, treatment of mice with troglitazone or knockdown of Smad3 in tumor cells both significantly inhibited TGF-β-induced experimental metastasis in Scid-Beige mice. Together, with the low toxicity profile of PPAR-γ ligands, our data demonstrates that these ligands may serve as potential therapeutic agents to inhibit metastasis.