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  • Title: Cell size and invasion in TGF-beta-induced epithelial to mesenchymal transition is regulated by activation of the mTOR pathway.
    Author: Lamouille S, Derynck R.
    Journal: J Cell Biol; 2007 Jul 30; 178(3):437-51. PubMed ID: 17646396.
    Abstract:
    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.
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