Inhibition of human MDA-MB-231 breast cancer cell invasion by matrix metalloproteinase 3 involves degradation of plasminogen.
Matrix metalloproteinase (MMP)-3 inhibited human MDA-MB-231 breast cancer cell invasion through reconstituted basement membrane in vitro. Inhibition of invasion was dependent upon plasminogen and MMP-3 activation, was impaired by the peptide MMP-3 inhibitor Ac-Arg-Cys-Gly-Val-Pro-Asp-NH2 and was associated with: rapid MMP-3-mediated plasminogen degradation to microplasminogen and angiostatin-like fragments; the removal of single-chain urokinase plasminogen activator from MDA-MB-231 cell membranes; impaired membrane plasminogen association; reduced rate of tissue plasminogen activator (t-PA) and membrane-mediated plasminogen activation; and reduced laminin-degrading capacity. Purified human plasminogen lysine binding site-1 (kringles 1-3) exhibited a similar capacity to inhibit MDA-MB-231 invasion, impair t-PA and cell membrane-mediated plasminogen activation and impair laminin degradation by plasmin. Our data provide evidence that MMP-3 can inhibit breast tumour cell invasion in vitro by a mechanism involving plasminogen degradation to fragments that limit plasminogen activation and the degradation of laminin. This supports the hypothesis that MMP-3, under certain conditions, may protect against tumour invasion, which would help to explain why MMP-3 expression, associated with benign and early stage breast tumours, is frequently lost in advanced stage, aggressive, breast disease.
Farina
Antonietta R
AR
Section of Molecular Pathology, Department of Experimental Medicine, University of L'Aquila, Italy.
Tacconelli
Antonella
A
Cappabianca
Lucia
L
Gulino
Alberto
A
Mackay
Andrew R
AR
D043168:Angiostatins; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D002462:Cell Membrane / Q000378:metabolism; D005260:Female; D006801:Humans; D007797:Laminin / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism* / Q000494:pharmacology; D009361:Neoplasm Invasiveness / Q000503:physiopathology; D010446:Peptide Fragments / Q000378:metabolism; D010958:Plasminogen / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D007797:Laminin; D010446:Peptide Fragments; D043168:Angiostatins; D010958:Plasminogen; D019278:Matrix Metalloproteinase 3