Tetrastatin, the NC1 Domain of the [alpha]4 Collagen Chain: A Novel Potent Anti-Tumor Matrikine

• Published in: PloS one 2012-04, Vol.7 (4), p.e29587
• Main Authors: Brassart-Pasco, Sylvie, Sénéchal, Karine, Thevenard, Jessica, Ramont, Laurent, Devy, Jérome, Di Stefano, Ludivine, Dupont-Deshorgue, Aurélie, Brézillon, Stéphane, Feru, Jezabel, Jazeron, Jean-François, Diebold, Marie-Danièle, Ricard-Blum, Sylvie, Maquart, François-Xavier, Monboisse, Jean Claude
• Format: Article
• Language: English
• Subjects: Analysis; Antibodies; Collagen; Integrins; Melanoma; Tumors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0029587

Background NC1 domains from [alpha]1, [alpha]2, [alpha]3 and [alpha]6(IV) collagen chains were shown to exert anti-tumor or anti-angiogenic activities, whereas the NC1 domain of the [alpha]4(IV) chain did not show such activities so far. Methodology/Principal Findings We demonstrate in the present paper that the NC1 [alpha]4(IV) domain exerts a potent anti-tumor activity both in vitro and in an experimental human melanoma model in vivo. The overexpression of NC1 [alpha]4(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 [alpha]4(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 [alpha]4(IV) reproduced the inhibitory effects of NC1 [alpha]4(IV) overexpression in UACC-903 cells but not in dermal fibroblasts. An anti-[alpha]v[beta]3 integrin blocking antibody inhibited cell adhesion on recombinant human NC1 [alpha]4(IV) substratum. The involvement of [alpha]v[beta]3 integrin in mediating NC1 [alpha]4(IV) effect was confirmed by surface plasmon resonance (SPR) binding assays showing that recombinant human NC1 [alpha]4(IV) binds to [alpha]v[beta]3 integrin (K.sub.D = 148±9.54 nM). Conclusion/Significance Collectively, our results demonstrate that the NC1 [alpha]4(IV) domain, named tetrastatin, is a new endogenous anti-tumor matrikine.