Prinomastat, a hydroxamate inhibitor of matrix metalloproteinases, has a complex effect on migration of breast carcinoma cells.

Abstract

Membrane type-1 matrix metalloproteinase (MT1-MMP) and alphavbeta3 integrin have been directly implicated in tumor cell dissemination and metastasis. We have demonstrated that in the case of breast carcinoma MCF7 cells co-expressing MT1-MMP and alphavbeta3 integrin, the proteinase processes the pro-alphav integrin subunit, thus facilitating alphavbeta3 integrin maturation and cell migration on vitronectin. Our findings show that cell surface MT1-MMP is a short-lived protein with a life span in the range of several hours. In contrast, turnover of alphavbeta3 integrin is much slower. The half-life of alphavbeta3 heterodimer is about 24 hr. This large difference in life span allowed us to distinguish between the effects of MT1-MMP on cell migration brought by matrix proteolysis from those imposed through alphavbeta3 integrin maturation. We then modulated the enzyme's activity by a potent hydroxamate MMP inhibitor, Prinomastat (AG3340), to analyze the divergent effects of MT1-MMP on cell migration. Although Prinomastat immediately blocked MT1-MMP-mediated matrix degradation, the pool of MT1-MMP-modified alphavbeta3 integrin molecules was still capable of mediating cell-matrix interactions. To our considerable surprise, inhibition of MT1-MMP-dependent vitronectin proteolysis by Prinomastat allowed a several-fold increase in migration of MCF7 cells co-expressing MT1-MMP and alphavbeta3 integrin. In contrast, long-term Prinomastat inhibition of MT1-MMP-dependent pro-alphav cleavage and thus alphavbeta3 integrin maturation strongly inhibited cell motility. Our studies suggest that MT1-MMP could actually promote cell migration via modification of the cell surface receptors, including alphavbeta3 integrin, rather than facilitate cell migration through direct cleavage of the matrix proteins.

• Authors: Elena I Deryugina, Boris I Ratnikov, Alex Y Strongin
• Journal: International journal of cancer (Int J Cancer) Vol. 104 Issue 5 Pg. 533-41 (May 01 2003) ISSN: 0020-7136 [Print] United States
• PMID: 12594807 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
• Copyright: Copyright 2003 Wiley-Liss, Inc.

Chemical References

• Antineoplastic Agents
• Enzyme Inhibitors
• Integrin alphaVbeta3
• Organic Chemicals
• Vitronectin
• prinomastat
• Matrix Metalloproteinases, Membrane-Associated
• Metalloendopeptidases

Topics

• Antineoplastic Agents (pharmacology)
• Breast Neoplasms (pathology)
• Cell Movement (drug effects)
• Enzyme Inhibitors (pharmacology)
• Humans
• Integrin alphaVbeta3 (metabolism)
• Matrix Metalloproteinases, Membrane-Associated
• Metalloendopeptidases (antagonists & inhibitors, metabolism)
• Organic Chemicals
• Tumor Cells, Cultured
• Vitronectin (metabolism)