The YSNSG cyclopeptide derived from tumstatin inhibits tumor angiogenesis by down-regulating endothelial cell migration

作者：Thevenard Jessica; Ramont Laurent; Devy Jerome; Brassart Bertrand; Dupont Deshorgue Aurelie; Floquet Nicolas; Schneider Laurence; Ouchani Farid; Terryn Christine; Maquart Francois Xavier; Monboisse Jean Claude; Brassart Pasco Sylvie^*

来源：International Journal of Cancer, 2010, 126(5): 1055-1066.

DOI：10.1002/ijc.24688

• tumstatin
• angiogenesis
• migration
• matrix metalloproteinases
• plasminogen activation system

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 heating 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 beta 1-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.

• 出版日期2010-3-1