ROS-NFkappaB mediates TGF-beta1-induced expression of urokinase-type plasminogen activator, matrix metalloproteinase-9 and cell invasion.
TGF-beta1 has been postulated as a pro-oncogenic factor in the late step of the tumoral progression. In transformed cells, TGF-beta1 enhances the capacity to degrade the extracellular matrix, cell invasiveness and epithelial-mesenchymal transition, which are crucial steps for metastasis. Urokinase-type plasminogen activator (uPA) and matrix metalloproteinase-9 (MMP-9) are critical components in cell migration and invasion induced by TGF-beta1, however, the exact mechanism by which TGF-beta1 regulates uPA and MMP-9 is not well elucidated so far. In the present study, we analyzed the role of ROS-NFkappaB, signal as mediator in the cell malignity enhancement by TGF-beta1. We found that TGF-beta1 activates NFkappaB, through Rac1-NOXs-ROS-dependent mechanism. Our results shows that TGF-beta1 stimulation of uPA and MMP-9 expression involve NOXs-dependent ROS and NFkappaB, activation, demonstrated by using DPI, NOXs inhibitor, ROS scavenger N-acetylcysteine and SN50, an NFkb inhibitor. Furthermore, we found that the inhibition of ROS and NFkappaB, abrogates TGF-beta1 stimulation of EMT, cell motility and invasion. Thus, ROS-NFkappaB acts as the crucial signal in TGF-beta1-induced uPA and MMP-9 expression thereby mediating the enhancement of cellular malignity by TGF-beta1.
Tobar
Nicolas
N
Laboratorio de Biología Celular, Instituto de Nutrición y Tecnología de los Alimentos, (INTA), Universidad de Chile, Santiago, Chile.
Villar
Victor
V
Santibanez
Juan F
JF
D021581:Active Transport, Cell Nucleus; D000818:Animals; D002461:Cell Line, Transformed; D002465:Cell Movement / Q000187:drug effects; D054338:Cell Transdifferentiation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D017930:Genes, Reporter; D015603:Keratinocytes / Q000187:drug effects / Q000201:enzymology*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D019255:NADPH Oxidases / Q000378:metabolism; D010641:Phenotype; D011401:Promoter Regions, Genetic; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D015854:Up-Regulation; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D017382:Reactive Oxygen Species; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D053773:Transforming Growth Factor beta1; D019255:NADPH Oxidases; D014568:Urokinase-Type Plasminogen Activator; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; D020830:rac1 GTP-Binding Protein