Carcinogenesis Advance Access published online on October 27, 2006
Carcinogenesis, doi:10.1093/carcin/bgl203
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1 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. 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-MMP-9 and -2, but not active forms of pro-MMP-2. MT1-MMP expression is regulated by NF-
Received April 17, 2006
Revised September 14, 2006
Accepted October 16, 2006
MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION
Methylseleninic acid inhibits PMA-stimulated pro-MMP-2 activation mediated by MT1-MMP expression and further tumor invasion through suppression of NF-
Jong-Min Park 1, Aeyung Kim 1, Jang-Hee Oh 1, and An-Sik Chung 1 *
B activation
An-Sik Chung, E-mail: aschung{at}kaist.ac.kr
Abstract 
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.
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