Sustained production of H(2)O(2) activates pro-matrix metalloproteinase-2 through receptor tyrosine kinases/phosphatidylinositol 3-kinase/NF-kappa B pathway.
A rate-limiting step of tumor cell metastasis is matrix degradation by active matrix metalloproteinases (MMPs). It is known that reactive oxygen species are involved in tumor metastasis. Sustained production of H(2)O(2) by phenazine methosulfate (PMS) induced activation of pro-MMP-2 through the induction of membrane type 1-MMP (MT1-MMP) expression in HT1080 cells. MMP-2, MMP-9, and tissue inhibitor of metalloproteinase-1 and -2 levels were changed negligibly by PMS. A one time treatment with H(2)O(2) did not induce activation of MMPs. It was also demonstrated that superoxide anions and hydroxyl radicals were not related to PMS action. PMS-induced pro-MMP-2 activation was regulated by the receptor tyrosine kinases, especially the receptors of platelet-derived growth factor and vascular endothelial growth factor, and downstream on the phosphatidylinositol 3-kinase/NF-kappa B pathway but not Ras, cAMP-dependent protein kinase, protein kinase C, and mitogen-activated protein kinases. PMS did not induce pro-MMP-2 activation in T98G and NIH3T3 cells. This may be related to a low level of MT1-MMP, indicating a threshold level of MT1-MMP is important for pro-MMP-2 activation. Furthermore, PMS increased cell motility and invasion but decreased cell-cell interaction. Cell-matrix interaction was not affected by PMS.
Yoon
Sang-Oh
SO
Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Taejon 305-701, South Korea.
Park
Soo-Jin
SJ
Yoon
Sun Young
SY
Yun
Chang-Hyun
CH
Chung
An-Sik
AS
D000818:Animals; D002448:Cell Adhesion; D002460:Cell Line; D002465:Cell Movement; D004792:Enzyme Precursors / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D008773:Methylphenazonium Methosulfate / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D017382:Reactive Oxygen Species; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism
D004792:Enzyme Precursors; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D013481:Superoxides; D019716:Tissue Inhibitor of Metalloproteinase-2; D008773:Methylphenazonium Methosulfate; D006861:Hydrogen Peroxide; D019869:Phosphatidylinositol 3-Kinases; D020794:Receptor Protein-Tyrosine Kinases; D020778:Matrix Metalloproteinase 2