(-)Epigallocatechin-3-Gallate Directly Inhibits MT1-MMP Activity, Leading to Accumulation of Nonactivated MMP-2 at the Cell Surface

Abstract

Consumption of green tea has been associated with prevention of cancer development, metastasis, and angiogenesis. Given the crucial role of the matrix metallo-proteinase-2 (MMP-2) on the degradation of the extracellular matrix instrumental to invasion, we examined the effect of the main flavanol present, (-)epigallocatechin-3-gallate (EGCG), on membrane-type 1 MMP (MT1-MMP), the receptor/activator of MMP-2. In-solution fluorimetric assay with activated MT1-MMP and gelatin-zymography with MT1-MMP catalytic domain alone and pro-MMP-2 activation by the same domain revealed dose-dependent inhibition of MT1-MMP at EGCG concentrations slightly lower than that reported to inhibit MMP-2 and MMP-9. Cytofluorimetry and immunolocalization revealed that EGCG does not impair MT1-MMP/TIMP-2/MMP-2 presence on the cell membrane. In the membrane extract of HT-1080 human fibrosarcoma cells, 10 μm EGCG caused a strong increase in MT1-MMP level and accumulation of pro-MMP-2 while leaving activated MMP-2 unchanged. EGCG thus exerts inhibition of MT1-MMP, which restrains activation of MMP-2; this may confer the antiangiogenic and antimetastatic activity associated with green tea.