Inhibition of matrix metalloproteinase 2 maturation and HT1080 invasiveness by a synthetic furin inhibitor.
The close correlation observed between matrix metalloproteinase 2 (MMP-2) activation and metastatic progression in various tumors suggests that MMP-2 is a 'master switch' triggering tumor spread. Recently, membrane type 1 MMP (MT1-MMP) was identified as a potential physiological activator of MMP-2. Like all other MMPs, MT1-MMP possesses a pro-domain which must be removed for the enzyme to acquire its catalytic potential. The presence of a typical recognition motif (RXKR) for the furin-like convertases at the end of its pro-domain suggests a potential role for these proteinases in MT1-MMP processing. In order to evaluate the implication of furin in pro-MT1-MMP processing, we treated HT1080 cells with a synthetic furin inhibitor and monitored their ability to activate pro-MMP-2 as well as their invasive potential. Our results demonstrated that the furin inhibitor decreased pro-MT1-MMP processing as well as pro-MMP-2 activation and cell invasiveness. Therefore, our data bring further evidence that furin is a key factor in the maturation of MMPs associated with the invasive and metastatic potential of tumor cells.
Maquoi
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E
Laboratoire de Biologie des Tumeurs et du Développement, Université de Liège, Belgium.
Noël
A
A
Frankenne
F
F
Angliker
H
H
Murphy
G
G
Foidart
J M
JM
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D005354:Fibrosarcoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D045683:Furin; D018093:Gelatinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D020778:Matrix Metalloproteinase 2; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D011480:Protease Inhibitors / Q000494:pharmacology*; D013381:Subtilisins / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured
C111573:1-oxodecyl-arginyl-valyl-lysyl-arginine chloromethyl ketone; D000590:Amino Acid Chloromethyl Ketones; D011480:Protease Inhibitors; D013381:Subtilisins; D045683:Furin; D018093:Gelatinases; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2