The angiostatic activity of interferon-inducible protein-10/CXCL10 in human melanoma depends on binding to CXCR3 but not to glycosaminoglycan.

Yang J, Richmond A
Mol Ther. 2004 9 (6): 846-55

PMID: 15194051 · PMCID: PMC2668261 · DOI:10.1016/j.ymthe.2004.01.010

Human interferon-inducible protein 10 (IP-10; HGMW-approved gene symbol CXCL10) is an ELR(-) CXC chemokine that contains binding domains for both the chemokine receptor CXCR3 and glycosaminoglycans. IP-10 has been recently demonstrated to be a potent angiostatic protein in vivo. Whether IP-10 exerts its angiostatic function through binding to CXCR3, glycosaminoglycans, or both, is not clear. To clarify this issue, we created expression constructs for mutants of IP-10 that exhibit partial (IP-10C) or total (IP-10C22) loss of binding to CXCR3 or loss of binding to glycosaminoglycans (IP-10H and IP-10C22H). The A375 human melanoma cell line was transfected with these expression vectors, and stable clones were selected and inoculated subcutaneously into nude mice. As expected, tumor cells secreting wild-type IP-10 showed remarkable reduction in tumor growth compared to control vector-transfected tumor cells. Surprisingly, mutation of IP-10 resulting in partial loss of receptor binding (IP-10C), or loss of GAG binding (IP-10H), did not significantly alter the ability to inhibit tumor growth. This tumor growth inhibition was associated with a reduction in microvessel density, leading to the observed increase in both tumor cell apoptosis and necrosis. In contrast, expression of the IP-10C22 mutant failed to inhibit melanoma tumor growth. These data suggest that CXCR3 receptor binding, but not glycosaminoglycan binding, is essential for the tumor angiostatic activity of IP-10. We conclude that the arginine 22 amino acid residue of IP-10 is essential for both CXCR3 binding and angiostasis.

MeSH Terms (24)

Amino Acid Motifs Amino Acid Sequence Amino Acid Substitution Angiogenesis Inhibitors Animals Binding, Competitive Capillaries Cell Line, Tumor Chemokine CXCL10 Chemokines, CXC Glycosaminoglycans Humans Melanoma Mice Mice, Nude Molecular Sequence Data Mutation Neoplasm Transplantation Neovascularization, Pathologic Platelet Endothelial Cell Adhesion Molecule-1 Protein Binding Receptors, Chemokine Receptors, CXCR3 Transfection

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