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Ciblage pharmacologique de la MT1-MMP dans les cellules tumorales cérébrales par l’actinonine, un inhibiteur de l’aminopeptidase N/CD13

Pharmacological targeting of MT1-MMP by actinonin in brain tumours

  • Mise Au Point
  • Published:
Bio tribune magazine

Résumé

L’actinonine, un inhibiteur de l’amino — peptidase N/CD13, possède également la capacité d’inhiber l’activité de certaines métalloprotéinases matricielles (MMP) solubles. Les effets de l’actinonine sur les MMP membranaires, telle la MT1-MMP, demeurent par contre peu connus. La MT1-MMP étant associée à une résistance à la chimiothérapie et à la radio thérapie au cours du dévelop — pement de tumeurs cérébrales, nous avons donc évalué son inhibition fonctionnelle par l’actinonine dans des cellules de glio blastome U87. Nous démontrons que l’actinonine inhibe l’activation de la proMMP-2 induite par la lectine concanavaline-A (ConA), tandis qu’elle est sans effet sur l’expression génique de MT1-MMP induite par la ConA. De plus, les effets posttranscriptionnels de l’actinonine pourraient s’exercer par le biais d’un autre régulateur membranaire d’activité pro — téasique de RECK (Reversion-inducing Cysteine-rich Protein with Kazal Motifs). L’actinonine exerce également un effet antagoniste sur une forme recombinante fonctionnelle de la MT1-MMP, dont l’expression constitutive entraîne l’activation de la proMMP-2. Ainsi, nous appor tons des preuves moléculaires supportant une nouvelle fonction inhi — bitrice de l’actinonine dans le ciblage direct de l’activation de la proMMP-2 par la MT1-MMP, une étape clé dans l’angio — génèse tumorale et dans l’acquisition du caractère infiltrant des tumeurs cérébrales.

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 membranebound MMPs remain unknown and that MT1-MMP has been linked to chemo- and radio-therapy resistance in brain tumour 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 may possibly be 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 tumour infiltration and in brain tumor-associated angiogenesis.

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Abbreviations

APN:

Aminopeptidase N

HUVEC:

Cellules endothéliales de la veine ombilicale humaine

ConA:

Concanavaline-A

MEC:

Matrice extracellulaire

MMP:

Métalloprotéinase matricielle

MT1-MMP:

Métalloprotéinase matricielle de type membranaire 1

RECK:

Reversion-inducing Cysteine-rich Protein with Kazal Motifs

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Authors and Affiliations

  1. Centre de recherche BioMED, Université du Québec à Montréal, Montréal, Québec, Canada

    A. Sina, S. Lord-Dufour & B. Annabi

  2. Centre de recherche Pharmaqam, Département de Chimie, Université du Québec à Montréal, Montréal, Québec, Canada

    R. Roy

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  1. A. Sina
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  2. S. Lord-Dufour
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  3. R. Roy
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  4. B. Annabi
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Correspondence to B. Annabi.

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Sina, A., Lord-Dufour, S., Roy, R. et al. Ciblage pharmacologique de la MT1-MMP dans les cellules tumorales cérébrales par l’actinonine, un inhibiteur de l’aminopeptidase N/CD13 . Bio trib. mag. 38, 39–45 (2011). https://doi.org/10.1007/s11834-011-0042-z

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