Inhibition of membrane-type 1 matrix metalloproteinase tyrosine phosphorylation blocks tumor progression in mice.
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.
Nyalendo
Carine
C
Laboratoire de Médecine Moléculaire, Université du Québec à Montréal, C.P. 8888, Succ. Centre-ville, Montréal, Québec H3C 3P8, Canada.
Sartelet
Hervé
H
Gingras
Denis
D
Béliveau
Richard
R
D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001710:Biotin / Q000031:analogs & derivatives* / Q000494:pharmacology; D020169:Caspases / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018450:Disease Progression; D005260:Female; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D010455:Peptides / Q000494:pharmacology*; D010766:Phosphorylation; D012513:Sarcoma, Experimental / Q000188:drug therapy; D014443:Tyrosine / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
C551584:ACM-14 peptide; D000970:Antineoplastic Agents; D010455:Peptides; D014443:Tyrosine; D001710:Biotin; D020169:Caspases; D053511:Matrix Metalloproteinase 14