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Research Articles: Therapeutics, Targets, and Development

Glycosaminoglycans and their synthetic mimetics inhibit RANTES-induced migration and invasion of human hepatoma cells

¹ EA 3410, Université Paris 13; ² Centre National de la Recherche Scientifique UMR 7033, Université Paris 13, Bobigny, France; ³ Laboratoire de Biochimie, Hôpital Jean Verdier, AP-HP, Bondy, France; ⁴ Centre National de la Recherche Scientifique UMR 7149, Université Paris 12-Val de Marne, Creteil, France; and ⁵ CEA Saclay, Gif-sur-Yvette, France

Requests for reprints: Nathalie Charnaux, EA 3410, Biothérapies Bénéfices et Risques, Université Paris 13, 74, rue Marcel Cachin, 93017 Bobigny, France. Phone: 33-1-48-38-73-53; Fax: 33-1-48-02-65-03. E-mail: nathalie.charnaux{at}jvr.aphp.fr

Abstract

The CC-chemokine regulated on activation, normal T-cell expressed, and presumably secreted (RANTES)/CCL5 mediates its biological activities through activation of G protein–coupled receptors, CCR1, CCR3, or CCR5, and binds to glycosaminoglycans. This study was undertaken to investigate whether this chemokine is involved in hepatoma cell migration or invasion and to modulate these effects in vitro by the use of glycosaminoglycan mimetics. We show that the human hepatoma Huh7 and Hep3B cells express RANTES/CCL5 G protein–coupled receptor CCR1 but not CCR3 nor CCR5. RANTES/CCL5 binding to these cells depends on CCR1 and glycosaminoglycans. Moreover, RANTES/CCL5 strongly stimulates the migration and the invasion of Huh7 cells and to a lesser extent that of Hep3B cells. RANTES/CCL5 also stimulates the tyrosine phosphorylation of focal adhesion kinase and activates matrix metalloproteinase-9 in Huh7 hepatoma cells, resulting in increased invasion of these cells. The fact that RANTES/CCL5-induced migration and invasion of Huh7 cells are both strongly inhibited by anti-CCR1 antibodies and heparin, as well as by ß-D-xyloside treatment of the cells, suggests that CCR1 and glycosaminoglycans are involved in these events. We then show by surface plasmon resonance that synthetic glycosaminoglycan mimetics, OTR4120 or OTR4131, directly bind to RANTES/CCL5. The preincubation of the chemokine with each of these mimetics strongly inhibited RANTES-induced migration and invasion of Huh7 cells. Therefore, targeting the RANTES-glycosaminoglycan interaction could be a new therapeutic approach for human hepatocellular carcinoma. [Mol Cancer Ther 2007;6(11):2948–58]

Grant support: Direction de la Recherche et des Enseignements Doctoraux (Ministère de l'Enseignement Supérieur et de la Recherche), Université Paris XIII.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: L. Gattegno and N. Charnaux contributed equally to this work.

Received 2/19/07; revised 7/ 4/07; accepted 9/17/07.