(-)Epigallocatechin-3-gallate directly inhibits MT1-MMP activity, leading to accumulation of nonactivated MMP-2 at the cell surface.
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.
Dell'Aica
Isabella
I
Department of Experimental Biomedical Sciences, Medical School of Padova, Padova, Italy.
Donà
Massimo
M
Sartor
Luigi
L
Pezzato
Elga
E
Garbisa
Spiridione
S
D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects* / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D005354:Fibrosarcoma; D005434:Flow Cytometry; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D018613:Microscopy, Confocal; D011480:Protease Inhibitors / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D011480:Protease Inhibitors; D002392:Catechin; C045651:epigallocatechin gallate; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2