We previously demonstrated that the CNYYSNS
peptide derived from
tumstatin inhibited in vivo
tumor progression. The YSNS motif formed a beta-turn crucial for
biological activity. More recently, a
YSNSG cyclopeptide with a constrained beta-turn on the YSNS residues was designed. Intraperitoneal administration of the
YSNSG cyclopeptide inhibited in vivo
melanoma progression more efficiently than the native linear
peptide. In the present article, we showed that the
YSNSG cyclopeptide also triggered an inhibition of in vivo
tumor neovascularization and we further analyzed its in vitroantiangiogenic effect. The
YSNSG cyclopeptide did not alter endothelial cell proliferation but inhibited cell migration by 83% in an in vitro wound healing model. The inhibition was mediated by a decrease in active
MT1-MMP at the migration front as well as a decrease in
u-PA and u-PAR expression. The
cyclopeptide also altered beta1-integrin distribution in endothelial cell lamellipodia, induced a strong decrease in the phosphorylated
focal adhesion kinase (p125(FAK)), disorganized
F-actin stress fibers and decreased the number of lamellipodia, resulting in a non migratory phenotype. Our results confirm the
YSNSG cyclopeptide as a potent
antitumor agent, through both the inhibition of invasive properties of
tumor cells and the antiangiogenic activity.