Glycosaminoglycans and their synthetic mimetics inhibit RANTES-induced migration and invasion of human hepatoma cells.
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 beta-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.
Sutton
Angela
A
EA 3410, Université Paris 13, Bobigny, France.
Friand
Veronique
V
Papy-Garcia
Dulce
D
Dagouassat
Maylis
M
Martin
Loïc
L
Vassy
Roger
R
Haddad
Oualid
O
Sainte-Catherine
Odile
O
Kraemer
Michel
M
Saffar
Line
L
Perret
Gerard Yves
GY
Courty
Jose
J
Gattegno
Liliane
L
Charnaux
Nathalie
N
D040761:Biomimetic Materials / Q000138:chemical synthesis / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D018946:Chemokine CCL5 / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D002633:Chemotaxis / Q000187:drug effects; D006025:Glycosaminoglycans / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology*; D009361:Neoplasm Invasiveness / Q000473:pathology
D018946:Chemokine CCL5; D006025:Glycosaminoglycans