Epigallocatechin-3-gallate directly inhibits MT1-MMP activity, leading to accumulation of nonactivated MMP-2 at the cell surface.

Dell'Aica I, Dona M, Sartor L, Pezzato E, Garbisa S.

Department of Experimental Biomedical Sciences, Medical School of Padova, Padova, Italy.

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 micro M 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.