THE DISINTEGRIN ERISTOSTATIN INTERFERES WITH INTEGRIN ALPHA-4-BETA-1 FUNCTION AND WITH EXPERIMENTAL METASTASIS OF HUMAN-MELANOMA CELLS

Peptides containing the integrin recognition sequence, RGD, call inhib it experimental metastasis of mouse melanoma cells, but the. integrin( s) affected in these experiments is unknown, Besides ''classical'' RGD -binding integrins such as alpha 5 beta 1 and alpha v beta 3, RGD has been reported to bind alpha 4 beta 1, and mAbs to alpha 4 beta 1 can i nhibit melanoma metastasis, We investigated the mode of action of the disintegrin eristostatin, an RGD-containing peptide isolated from snak e venom, in a human melanoma experimental metastasis model, Lung colon ization following i.v. injection of MV3 cells in nude mice was strongl y inhibited by eristostatin. MV3 cells bound FITC-eristostatin and adh ered to aristostatin-coated wells, This adhesion was partially inhibit ed by a GRGDSP peptide and by alpha 4 mAb. finding of FITC-eristostati n to Jurkat cells and adhesion of Jurkat (but not K562) cells to erist ostatin-coated wells further suggested that eristostatin binds alpha 4 beta 1, even though, again, alpha 4 mAb only partially inhibited adhe sion, Expression of alpha 4 beta 1 was enhanced in metastatic melanoma cells compared to normal melanocytes and nonmetastatic melanoma cells , Finally, eristostatin inhibited adhesion of both MV3 and CHO alpha 4 cells to the alpha 4 beta 1-ligand VCAM-1, while adhesion to other li gands via other integrins was not affected, These findings demonstrate that inhibition of melanoma cell metastasis by RGD-containing peptide s such as eristostatin, may be due to interference with alpha 4 beta 1 -VCAM binding, in addition to inhibition of the classical RGD-binding integrins. (C) 1998 Academic Press.