Cell-based evidence for aminopeptidase N/CD13 inhibitor actinonin targeting of MT1-MMP-mediated proMMP-2 activation.
Recent profiling has identified the aminopeptidase N/CD13 inhibitor actinonin as a selective soluble secreted matrix metalloproteinase (MMP) inhibitor. Given that actinonin's effects against membrane-bound MMPs remain unknown and that MT1-MMP has been linked to chemo- and radio-therapy resistance in brain tumor development, we therefore assessed MT1-MMP functional inhibition by actinonin in U87 glioblastoma cells. We show that actinonin inhibits concanavalin-A (ConA)-induced proMMP-2 activation, while it does not inhibit ConA-induced MT1-MMP gene expression suggesting post-transcriptional effects of the drug possibly mediated through the membrane-anchored protease regulator RECK. Specific gene silencing of MT1-MMP with siRNA abrogated the ability of ConA to activate proMMP-2. Functional recombinant MT1-MMP whose constitutive expression led to proMMP-2 activation was also efficiently antagonized by actinonin. We provide evidence for actinonin's new therapeutic application in the direct targeting of MT1-MMP-mediated proMMP-2 activation, an essential step in both brain tumor infiltration and in brain tumor-associated angiogenesis.
Sina
Asmaa
A
Laboratoire d'Oncologie Moléculaire, Département de Chimie, Centre de Recherche BioMED, Université du Québec à Montréal, C.P. 8888, Succ. Centre-ville Montréal, Québec, Canada H3C 3P8.
Lord-Dufour
Simon
S
Annabi
Borhane
B
D000970:Antineoplastic Agents / Q000494:pharmacology*; D018826:CD13 Antigens / Q000037:antagonists & inhibitors / Q000378:metabolism*; D045744:Cell Line, Tumor; D003208:Concanavalin A / Q000494:pharmacology; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000378:metabolism*; D005909:Glioblastoma; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D053402:PHEX Phosphate Regulating Neutral Endopeptidase / Q000378:metabolism; D011485:Protein Binding
D000970:Antineoplastic Agents; D004792:Enzyme Precursors; D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D003208:Concanavalin A; D018826:CD13 Antigens; D053402:PHEX Phosphate Regulating Neutral Endopeptidase; D020778:Matrix Metalloproteinase 2; D053511:Matrix Metalloproteinase 14; C010531:actinonin