Cell size and invasion in TGF-beta-induced epithelial to mesenchymal transition is regulated by activation of the mTOR pathway.
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.
Lamouille
Samy
S
Department of Cell and Tissue Biology, Program in Cell Biology, University of California, San Francisco, San Francisco, CA 94143, USA.
Derynck
Rik
R
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion / Q000502:physiology; D018797:Cell Cycle Proteins; D002465:Cell Movement / Q000502:physiology; D048429:Cell Size; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology; D004848:Epithelium / Q000502:physiology*; D039642:Eukaryotic Initiation Factors; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008321:Mammary Glands, Animal / Q000033:anatomy & histology; D008648:Mesoderm / Q000502:physiology*; D051379:Mice; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D020123:Sirolimus / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D000903:Antibiotics, Antineoplastic; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C499527:Eif4ebp1 protein, mouse; D039642:Eukaryotic Initiation Factors; D010750:Phosphoproteins; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus