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

Abstract

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.

Geniposide inhibits interleukin-6 and interleukin-8 production in lipopolysaccharide-induced human umbilical vein endothelial cells by blocking p38 and ERK1/2 signaling pathways

“…On the other hand, this excessive migration toward inflammatory sites will aggravate inflammation responses because of the over-production of pro-inflammatory cytokines in endothelial cells. Also, endothelial cell migration is vital for tumor angiogenesis and thus promotes the occurrence and progression of tumors [31]. As early chemotactic signals in acute-phase inflammation reaction, IL-6 and IL-8 play crucial roles in recruiting immune cells to the site of inflammation.…”

Tetrastatin, the NC1 Domain of the α4(IV) Collagen Chain: A Novel Potent Anti-Tumor Matrikine

“…The anti-tumor activity of tumstatin resided in a short peptide sequence, CNYYSNS, located within its C-terminal part [32], [33]. The sequence was used as a basis to design and develop a synthetic cyclopeptide able to exert anti-tumor and anti-angiogenic activities [34], [35].…”

Anti-Angiogenic Peptides for Cancer Therapeutics

“…Thevenard et al demonstrated that a shorter fragment of the tumstatin sequence, YSNS, forms a β-sheet which is important for biological activity and that a cyclized version of YSNSG formed a very stable and active structure [37, 38]. This compound showed activity in inhibiting adhesion and migration of endothelial and melanoma cells.…”