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: Jong-Min Park, Aeyung Kim, Jang-Hee Oh, An-Sik Chung
• Journal: Carcinogenesis (Carcinogenesis) Vol. 28 Issue 4 Pg. 837-47 (Apr 2007) ISSN: 0143-3334 [Print] England
• PMID: 17071627 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Carcinogens
• Enzyme Precursors
• NF-kappa B
• Organoselenium Compounds
• Reactive Oxygen Species
• Tissue Inhibitor of Metalloproteinase-2
• methylselenic acid
• Matrix Metalloproteinase 2
• MMP14 protein, human
• Matrix Metalloproteinase 14
• Tetradecanoylphorbol Acetate

Topics

• Carcinogens (pharmacology)
• Dose-Response Relationship, Drug
• Electrophoretic Mobility Shift Assay
• Enzyme Activation (drug effects)
• Enzyme Precursors (metabolism)
• Fibrosarcoma (metabolism, pathology)
• Humans
• Matrix Metalloproteinase 14 (genetics, metabolism)
• Matrix Metalloproteinase 2 (metabolism)
• NF-kappa B (genetics, metabolism)
• Neoplasm Invasiveness
• Organoselenium Compounds (pharmacology)
• Reactive Oxygen Species (metabolism)
• Tetradecanoylphorbol Acetate (pharmacology)
• Tissue Inhibitor of Metalloproteinase-2 (metabolism)
• Tumor Cells, Cultured (drug effects)