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A New Type of Antimetastatic Peptide Derived from Fibronectin¹

Departments of Patho-Physiology [R. K., T. I., S. K., F. O., T. K., F. F.] and Analytical Chemistry [R. K., S. K., H. N.], Faculty of Pharmaceutical Sciences, Science University of Tokyo, Tokyo 162-0826; Department of Applied Chemistry, Faculty of Science, Science University of Tokyo, Tokyo 162-8601 [M. U.]; and Research Center for Material Cycles and Waste management, National Institute of Environmental Studies, Tsukuba-shi, Ibaraki 305-0053 [S. G.], Japan

Purpose: We found previously that fibronectin (FN) has a cryptic functional site (YTIYVIAL sequence within the 14th type III repeat) opposing cell adhesion to extracellular matrix. A 22-mer FN peptide containing this site, termed FNIII14, inhibits ß1 integrin-mediated adhesion without binding to integrins. The present study shows that FNIII14 has the potential to prevent lymphoma cell metastasis.

Experimental Design: Antimetastatic effect of FNIII14 has been evaluated through in vitro or in vivo experiments.

Results: FNIII14 inhibited the integrin 4ß1-mediated B lymphoma Ramos cell adhesion to VCAM-1 on venule endothelial cells, as well as to FN. Murine T lymphoma L5178Y-ML25 cells, which are known to metastasize to liver and spleen, preferentially adhered to vitronectin (VN) and migrated toward VN concentration gradients. FNIII14 abrogated both the integrin vß3-mediated adhesion and migration of L5178Y-ML25 cells. Inhibition of the vß3mediated L5178Y-ML25 cell adhesion by FNIII14 was reversed by phenylarsine oxide, a protein tyrosine phosphatase inhibitor. In addition, FNIII14 abrogated the VN-stimulated tyrosine phosphorylation of intracellular signaling proteins, including focal adhesion kinase (p125^FAK) and paxillin, suggesting that such a diversity of FNIII14 effects might be because of the negative regulation of p125^FAK and paxillin tyrosine phosphorylation, which has been involved in adhesion signals transduced by different integrins. The in vivo experiment using a murine metastasis model showed that FNIII14 would inhibit liver and spleen metastases of L5178Y-ML25 cells at a dose much lower than that of RGDS.

Conclusions: FNIII14 might be applicable as a new type of antimetastatic agent distinct from integrin-binding peptides.

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