The YSNSG cyclopeptide derived from tumstatin inhibits tumor angiogenesis by down-regulating endothelial cell migration.
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.
Thevenard
Jessica
J
CNRS UMR 6237, Université de Reims Champagne-Ardenne, CHU de Reims, Reims, France.
Ramont
Laurent
L
Devy
Jérome
J
Brassart
Bertrand
B
Dupont-Deshorgue
Aurélie
A
Floquet
Nicolas
N
Schneider
Laurence
L
Ouchani
Farid
F
Terryn
Christine
C
Maquart
François-Xavier
FX
Monboisse
Jean-Claude
JC
Brassart-Pasco
Sylvie
S
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001324:Autoantigens / Q000737:chemistry; D015153:Blotting, Western; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D024141:Collagen Type IV / Q000737:chemistry; D015536:Down-Regulation; D042783:Endothelial Cells / Q000187:drug effects*; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D053511:Matrix Metalloproteinase 14 / Q000187:drug effects / Q000378:metabolism; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D010456:Peptides, Cyclic / Q000494:pharmacology*; D055293:Receptors, Urokinase Plasminogen Activator / Q000187:drug effects / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000187:drug effects / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D001324:Autoantigens; D024141:Collagen Type IV; D010456:Peptides, Cyclic; D055293:Receptors, Urokinase Plasminogen Activator; C521292:YSNSG cyclopeptide; C057112:type IV collagen alpha3 chain; D014568:Urokinase-Type Plasminogen Activator; D053511:Matrix Metalloproteinase 14