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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • CD13 Antigens / antagonists & inhibitors
  • CD13 Antigens / metabolism*
  • Cell Line, Tumor
  • Concanavalin A / pharmacology
  • Enzyme Activation
  • Enzyme Precursors / metabolism*
  • Glioblastoma
  • Humans
  • Hydroxamic Acids / pharmacology
  • Matrix Metalloproteinase 14 / metabolism*
  • Matrix Metalloproteinase 2 / metabolism*
  • Matrix Metalloproteinase Inhibitors
  • PHEX Phosphate Regulating Neutral Endopeptidase / metabolism
  • Protein Binding


  • Antineoplastic Agents
  • Enzyme Precursors
  • Hydroxamic Acids
  • Matrix Metalloproteinase Inhibitors
  • Concanavalin A
  • CD13 Antigens
  • PHEX Phosphate Regulating Neutral Endopeptidase
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 14
  • actinonin