Lamouille Samy, Derynck Rik
Department of Cell and Tissue Biology, Program in Cell Biology, University of California, San Francisco, San Francisco, CA 94143, USA.
J Cell Biol. 2007 Jul 30;178(3):437-51. doi: 10.1083/jcb.200611146. Epub 2007 Jul 23.
Epithelial to mesenchymal transition (EMT) occurs during development and cancer progression to metastasis and results in enhanced cell motility and invasion. Transforming growth factor-beta (TGF-beta) induces EMT through Smads, leading to transcriptional regulation, and through non-Smad pathways. We observe that TGF-beta induces increased cell size and protein content during EMT. This translational regulation results from activation by TGF-beta of mammalian target of rapamycin (mTOR) through phosphatidylinositol 3-kinase and Akt, leading to the phosphorylation of S6 kinase 1 and eukaryotic initiation factor 4E-binding protein 1, which are direct regulators of translation initiation. Rapamycin, a specific inhibitor of mTOR complex 1, inhibits the TGF-beta-induced translation pathway and increase in cell size without affecting the EMT phenotype. Additionally, rapamycin decreases the migratory and invasive behavior of cells that accompany TGF-beta-induced EMT. The TGF-beta-induced translation pathway through mTOR complements the transcription pathway through Smads. Activation of mTOR by TGF-beta, which leads to increased cell size and invasion, adds to the role of TGF-beta-induced EMT in cancer progression and may represent a therapeutic opportunity for rapamycin analogues in cancer.
上皮-间质转化（EMT）发生于发育过程以及癌症进展至转移阶段，会导致细胞运动性和侵袭能力增强。转化生长因子-β（TGF-β）通过Smads诱导EMT，引发转录调控，并通过非Smad途径发挥作用。我们观察到，TGF-β在EMT过程中会诱导细胞体积和蛋白质含量增加。这种翻译调控是由TGF-β通过磷脂酰肌醇3-激酶和Akt激活雷帕霉素哺乳动物靶蛋白（mTOR）所致，进而导致S6激酶1和真核起始因子4E结合蛋白1磷酸化，这两种蛋白是翻译起始的直接调节因子。雷帕霉素是mTOR复合物1的特异性抑制剂，可抑制TGF-β诱导的翻译途径以及细胞体积增大，且不影响EMT表型。此外，雷帕霉素可降低伴随TGF-β诱导的EMT的细胞迁移和侵袭行为。TGF-β通过mTOR诱导的翻译途径补充了通过Smads的转录途径。TGF-β对mTOR的激活导致细胞体积增大和侵袭增加，这进一步凸显了TGF-β诱导的EMT在癌症进展中的作用，并且可能为雷帕霉素类似物在癌症治疗中提供契机。
