Studies on inhibitory effects of methylselenium compounds on pro-MMP-2 activation and tumor invasion

Abstract

Selenium, an essential biological trace element, reduces the incidence of cancer. Metastasis is a major cause of death among cancer patients. The main groups of proteolytic enzymes involved in the tumor invasion are matrix metalloproteinases (MMPs). Significant positive correlations have been found between MMP expression and various indicators of poor prognosis in virtually all types of cancer. Previous studies show that selenite inhibits tumor invasion by suppressing the expression of matrix metalloproteinases -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, it was demonstrated that MSeA suppressed pro-MMP-2 activation in a dose-dependent manner induced by 12-O-tetradecanoylphorbol-13-acetate (PMA), and further decreased 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 the tissue inhibitor of metalloproteinase-2 (TIMP-2) as an adaptor, by forming a trimolecular complex on the cell surface. MSeA blocked MT1-MMP expression in a dose-dependent manner, but did not TIMP-2 expression. MMP-9 and TIMP-1 levels were not affected by treatment with MSeA. Selenite decreased protein levels of both pro-MMP-9 and -2, but did not active forms of pro-MMP-2. MT1-MMP expression is regulated by NF-κB. The nuclear DNA-NF-κB complex by EMSA was increased after 30~180 min of PMA treatment and MSeA diminished nuclear localization of the NF-κB complex. MSeA inhibits PMA-induced translocation of p65 to the nucleus through blockage of IκB-α and p65 phosphorylation. Treatment with PDTC (a general inhibitor of NF-κB) reduced pro-MMP-2 activation and MT1-MMP expression induced by PMA. These data show that the effect of MSeA on MT1-MMP expression is mediated through suppression of NF-κB activity. Pretreatment with MSeA blocked the activation of pro-MMP-2 and NF-κ...