Tetrastatin, the NC1 domain of the alpha4(IV) collagen chain: a novel potent anti-tumor matrikine.
Fiche publication
Date publication
janvier 2012
Auteurs
Membres identifiés du Cancéropôle Est :
Dr BRASSART-PASCO Sylvie, Dr BREZILLON Stéphane, Dr DEVY Jérôme, Dr MONBOISSE Jean-Claude, Pr RAMONT Laurent, Dr THEVENARD-DEVY Jessica
Tous les auteurs :
Brassart-Pasco S, Senechal K, Thevenard J, Ramont L, Devy J, Di Stefano L, Dupont-Deshorgue A, Brezillon S, Feru J, Jazeron JF, Diebold MD, Ricard-Blum S, Maquart FX, Monboisse JC
Lien Pubmed
Résumé
BACKGROUND: NC1 domains from alpha1, alpha2, alpha3 and alpha6(IV) collagen chains were shown to exert anti-tumor or anti-angiogenic activities, whereas the NC1 domain of the alpha4(IV) chain did not show such activities so far. METHODOLOGY/PRINCIPAL FINDINGS: We demonstrate in the present paper that the NC1 alpha4(IV) domain exerts a potent anti-tumor activity both in vitro and in an experimental human melanoma model in vivo. The overexpression of NC1 alpha4(IV) in human UACC-903 melanoma cells strongly inhibited their in vitro proliferative (-38%) and invasive (-52%) properties. MT1-MMP activation was largely decreased and its cellular distribution was modified, resulting in a loss of expression at the migration front associated with a loss of migratory phenotype. In an in vivo xenograft model in athymic nude mice, the subcutaneous injection of NC1 alpha4(IV)-overexpressing melanoma cells induced significantly smaller tumors (-80% tumor volume) than the Mock cells, due to a strong inhibition of tumor growth. Exogenously added recombinant human NC1 alpha4(IV) reproduced the inhibitory effects of NC1 alpha4(IV) overexpression in UACC-903 cells but not in dermal fibroblasts. An anti-alphavbeta3 integrin blocking antibody inhibited cell adhesion on recombinant human NC1 alpha4(IV) substratum. The involvement of alphavbeta3 integrin in mediating NC1 alpha4(IV) effect was confirmed by surface plasmon resonance (SPR) binding assays showing that recombinant human NC1 alpha4(IV) binds to alphavbeta3 integrin (K(D) = 148 +/- 9.54 nM). CONCLUSION/SIGNIFICANCE: Collectively, our results demonstrate that the NC1 alpha4(IV) domain, named tetrastatin, is a new endogenous anti-tumor matrikine.
Référence
PLoS One. 2012;7(4):e29587