TGF-β1 increases invasiveness of SW1990 cells through Rac1/ROS/NF-κB/IL-6/MMP-2 |
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Authors: | Marcelo G Binker Andres A Binker-Cosen Herbert Y Gaisano Rodica H de Cosen Laura I Cosen-Binker |
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Institution: | aDepartments of Medicine and Physiology, University of Toronto, Toronto, Ontario, Canada M5S 1A8;bCBRHC Research Center, Buenos Aires, Argentina |
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Abstract: | Human pancreatic cancer invasion and metastasis have been found to correlate with increased levels of active matrix metalloproteinase 2 (MMP-2). The multifunctional cytokine transforming growth factor beta 1 (TGF-β1) has been shown to increase both secretion of MMP-2 and invasion by several pancreatic cancer cell types. In the present study, we investigated the signaling pathway involved in TGF-β1-promoted MMP-2 secretion and invasion by human pancreatic cancer cells SW1990. Using specific inhibitors, we found that stimulation of these tumor cells with TGF-β1 induced secretion and activation of the collagenase MMP-2, which was required for TGF-β1-stimulated invasion. Our results also indicate that signaling events involved in TGF-β1-enhanced SW1990 invasiveness comprehend activation of Rac1 followed by generation of reactive oxygen species through nicotinamide adenine dinucleotide phosphate-oxidase, activation of nuclear factor-kappa beta, release of interleukin-6, and secretion and activation of MMP-2. |
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Keywords: | Abbreviations: DPI diphenyleneiodonium IL-6 interleukin-6 ILO Ilomastat MMP matrix metalloproteinase NAC N-acetylcysteine NADPH nicotinamide adenine dinucleotide phosphate-oxidase NF-κB nuclear factor-kappa beta NSC NSC23766 PDTC pyrridoline dithiocarbamate ROS reactive oxygen species TGF-β1 transforming growth factor-beta 1 |
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