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The YSNSG cyclopeptide derived from tumstatin inhibits tumor angiogenesis by down‐regulating endothelial cell migration
Author(s) -
Thevenard Jessica,
Ramont Laurent,
Devy Jérome,
Brassart Bertrand,
DupontDeshorgue Aurélie,
Floquet Nicolas,
Schneider Laurence,
Ouchani Farid,
Terryn Christine,
Maquart FrançoisXavier,
Monboisse JeanClaude,
BrassartPasco Sylvie
Publication year - 2009
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.24688
Subject(s) - angiogenesis , in vivo , cell migration , cancer research , integrin , in vitro , endothelial stem cell , focal adhesion , actin cytoskeleton , lamellipodium , peptide , cell growth , cell , biology , microbiology and biotechnology , chemistry , signal transduction , biochemistry , cytoskeleton
We previously demonstrated that the CNYYSNS peptide derived from tumstatin inhibited in vivo tumor progression. The YSNS motif formed a β‐turn crucial for biological activity. More recently, a YSNSG cyclopeptide with a constrained β‐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 vitro antiangiogenic 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 β1‐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.