title: Methylseleninic acid inhibits PMA-stimulated pro-MMP-2 activation mediated by MT1-MMP expression and further tumor invasion through suppression of NF-kappaB activation.
abstract: Selenium, an essential biological trace element, reduces the incidence of cancer. Our previous studies show that selenite inhibits tumor invasion by suppressing the expression of matrix metalloproteinases (MMP) -2 and -9. Methylseleninic acid (MSeA), an immediate precursor of methylselenol, inhibits tumor cell growth in vitro and mammary carcinogenesis in vivo. In this study, we demonstrate that MSeA suppresses pro-MMP-2 activation in a dose-dependent manner induced by 12-O-tetradecanoylphorbol-13-acetate (PMA), and further decreases the invasiveness of HT1080 tumor cells. Membrane type-1-MMP (MT1-MMP) is a crucial element in the process of pro-MMP-2 activation. Pro-MMP-2 binds MT1-MMP, using tissue inhibitor of metalloproteinase-2 (TIMP-2) as an adaptor, by forming a trimolecular complex on the cell surface. MSeA blocked MT1-MMP in a dose-dependent manner, but not TIMP-2 expression. MMP-9 and TIMP-1 levels were not affected by MSeA. Selenite induced a decrease in protein levels of both pro-MMPs -9 and -2, but not active forms of pro-MMP-2. MT1-MMP expression is regulated by NF-kappaB. Our data show that the effect of MSeA on MT1-MMP expression is mediated through suppression of NF-kappaB activity. Methylselenol generated by selenomethionine (SeMet) and methioninase (METase) inhibited pro-MMP-2 activation induced by PMA, confirming the effect of MSeA on pro-MMP-2 activity. Moreover, ROS production induced by PMA was partly decreased in the presence of MSeA. This suppression of ROS production may be related to diminished NF-kappaB activity. Thus, our results suggest that MSeA blocks tumor invasion in vitro via inhibiting pro-MMP-2 activation mediated by suppression of MT1-MMP expression, which is regulated by the NF-kappaB signal pathway.
authors.affiliation: Department of Biological Science, Biochemical Toxicology Lab, Korea Advanced Institute of Science and Technology, 373-1, Guseong-dong, Yuseong-gu, Daejeon, 305-701, South Korea.
authors.forename: Jong-Min
authors.initials: JM
authors.lastname: Park
authors.forename: Aeyung
authors.initials: A
authors.lastname: Kim
authors.forename: Jang-Hee
authors.initials: JH
authors.lastname: Oh
authors.forename: An-Sik
authors.initials: AS
authors.lastname: Chung
mesh_terms: D002273:Carcinogens / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D024202:Electrophoretic Mobility Shift Assay; D004789:Enzyme Activation / Q000187:drug effects; D004792:Enzyme Precursors / Q000378:metabolism; D005354:Fibrosarcoma / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D016566:Organoselenium Compounds / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D002273:Carcinogens; D004792:Enzyme Precursors; D016328:NF-kappa B; D016566:Organoselenium Compounds; D017382:Reactive Oxygen Species; D019716:Tissue Inhibitor of Metalloproteinase-2; C008493:methylselenic acid; D020778:Matrix Metalloproteinase 2; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14; D013755:Tetradecanoylphorbol Acetate