We have recently shown that green tea polyphenols, and especially (−)-epigallocatechin 3-gallate (EGCg), acted as potent inhibitors of matrix metalloproteinase activities as well as of proMMP-2 activation (M. Demeule, M. Brossard, M. Page, D. Gingras, R. Beliveau, Biochim. Biophys. Acta 1478 (2000)). In the present work, we sought to examine the involvement of MT1-MMP in the EGCg-induced inhibition of proMMP-2 activation. The incubation of U-87 glioblastoma cells in the presence of concanavalin A or cytochalasin D, two potent activators of MT1-MMP, resulted in proMMP-2 activation that was correlated with the cell surface proteolytic processing of MT1-MMP to its inactive 43 kDa form. Addition of EGCg strongly inhibited the MT1-MMP-dependent proMMP-2 activation. The inhibitory effect of EGCg on MT1-MMP was also demonstrated by the down-regulation of MT1-MMP transcript levels and by the inhibition of MT1-MMP-driven cell migration of transfected COS-7 cells. These observations suggest that this catechin may act at both the MT1-MMP gene and protein expression levels. In addition, treatment of cells with non-cytotoxic doses of EGCg significantly reduced the amount of secreted proMMP-2, and led to a concomitant increase in intracellular levels of that protein. This effect was similar to that observed using well-characterized secretion inhibitors such as brefeldin A and manumycin, suggesting that EGCg could also potentially act on intracellular secretory pathways. Taken together, these results indicate that EGCg targets multiple MMP-mediated cellular events in cancer cells and provides a new mechanism for the anticancer properties of that molecule.
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