Carcinogenesis Advance Access originally published online on October 27, 2006
Carcinogenesis 2007 28(4):837-847; doi:10.1093/carcin/bgl203
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Methylseleninic acid inhibits PMA-stimulated pro-MMP-2 activation mediated by MT1-MMP expression and further tumor invasion through suppression of NF-
B activation
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
*To whom correspondence should be addressed. Email: aschung{at}kaist.ac.kr
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-
B. Our data show that the effect of MSeA on MT1-MMP expression is mediated through suppression of NF-B 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-B 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-B signal pathway.
Abbreviations: DCFH-DA, dichlorofluorescin diacetate; DDC, diethyldithiocarbamic acid; METase, Methioninase; MMP, matrix metalloproteinase; MSeA, Methylseleninic acid; MT1-MMP, membrane-type 1-matrix metalloproteinase; PMA, 12-O-tetradecanoyl-phorbol-13-acetate; ROS, reactive oxygen species; SeMet, selenomethionine; TIMP, tissue inhibitor of metalloproteinase
Received April 17, 2006; revised September 14, 2006; accepted October 16, 2006.
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