Inhibition of membrane-type 1 matrix metalloproteinase tyrosine phosphorylation blocks tumor progression in mice.

ABSTRACT

We recently reported that membrane-type 1 matrix metalloproteinase (MT1-MMP) is phosphorylated on its unique cytoplasmic tyrosine residue but the contribution of this event to tumor progression remains unclear. In this work, we show that the non phosphorylizable cell-permeable peptide antennapedia-coupled cytoplasmic MMP-14 (ACM-14), consisting of the mutated (Y573F) cytoplasmic domain of MT1-MMP coupled to antennapedia, inhibits tyrosine phosphorylation of the enzyme and markedly reduces tumor cell proliferation within 3D type I collagen matrices. Interestingly, administration of ACM-14 to mice markedly delays tumor progression and increases survival, these antitumor actions being associated with the induction of extensive tumor necrosis. Overall, these findings suggest that inhibition of MT1-MMP tyrosine phosphorylation may represent an attractive strategy for the development of novel anticancer drugs.