Tetrastatin, the NC1 domain of the ?4(IV) collagen chain: a novel potent anti-tumor matrikine.

ABSTRACT:

Background

NC1 domains from ?1, ?2, ?3 and ?6(IV) collagen chains were shown to exert anti-tumor or anti-angiogenic activities, whereas the NC1 domain of the ?4(IV) chain did not show such activities so far.

Methodology/principal findings

We demonstrate in the present paper that the NC1 ?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 ?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 ?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 ?4(IV) reproduced the inhibitory effects of NC1 ?4(IV) overexpression in UACC-903 cells but not in dermal fibroblasts. An anti-?v?3 integrin blocking antibody inhibited cell adhesion on recombinant human NC1 ?4(IV) substratum. The involvement of ?v?3 integrin in mediating NC1 ?4(IV) effect was confirmed by surface plasmon resonance (SPR) binding assays showing that recombinant human NC1 ?4(IV) binds to ?v?3 integrin (K(D) = 148 ± 9.54 nM).

Conclusion/significance

Collectively, our results demonstrate that the NC1 ?4(IV) domain, named tetrastatin, is a new endogenous anti-tumor matrikine.

SUBMITTER: Brassart-Pasco S 

PROVIDER: S-EPMC3335157 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature