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Cancer Lett. 2009 Jul 8;279(2):171-6. doi: 10.1016/j.canlet.2009.01.032. Epub 2009 Mar 4.

Cell-based evidence for aminopeptidase N/CD13 inhibitor actinonin targeting of MT1-MMP-mediated proMMP-2 activation.

Author information

1
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.

Abstract

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.

PMID:
19264392
DOI:
10.1016/j.canlet.2009.01.032
[Indexed for MEDLINE]

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