TY - JOUR
T1 - A urokinase receptor-derived peptide inhibiting VEGF-dependent directional migration and vascular sprouting
AU - Bifulco, Katia
AU - Longanesi-Cattani, Immacolata
AU - Liguori, Eleonora
AU - Arra, Claudio
AU - Rea, Domenica
AU - Masucci, Maria Teresa
AU - De Rosa, Mario
AU - Pavone, Vincenzo
AU - Stoppelli, Maria Patrizia
AU - Carriero, Maria Vincenza
PY - 2013/10
Y1 - 2013/10
N2 - The receptor for the urokinase-type plasminogen activator (uPAR) is a widely recognized master regulator of cell migration, and uPAR88-92 is the minimal sequence required to induce cell motility. We previously showed that soluble formsofuPARelicitangiogenic responses throughtheiruPAR 88-92 chemotactic sequenceandthat the synthetic peptide SRSRY exerts similar effects. By a drug design approach, based on the conformational analysis of the uPAR88-92 sequence, we developed peptides (pERERY, RERY, and RERF) that potently inhibit signaling triggered by uPAR88-92. In this study, we present evidence that these peptides are endowed also with a clear-cut antiangiogenic activity, although to different extents. The most active, RERF, prevents tube formation by human endothelial cells exposed to SRSRY. RERF also inhibits VEGF-triggered endothelial cell migration and cord-like formation in a dose-dependentmanner, starting in the femtomolar range. RERF prevents F-actin polymerization, recruitment of αvβ3 integrin at focal adhesions, and αvβ3/VEGFR2 complex formation in endothelial cells exposed to VEGF. Atmolecular level, the inhibitory effect of RERF on VEGF signaling is shown by the decreased amount of phospho-FAK and phospho-Akt in VEGF-treated cells. In vivo, RERF prevents VEGF-dependent capillary sprouts originating from the host vessels that invaded angioreactors implanted in mice and neovascularization induced by subcorneal implantation of pellets containingVEGFin rabbits.Consistently, RERF reduced the growth and vascularization rate of tumors formed by HT1080 cells injected subcutaneously in the flanks of nude mice, indicating that RERF is a promising therapeutic agent for the control of diseases fuelled by excessive angiogenesis such as cancer.
AB - The receptor for the urokinase-type plasminogen activator (uPAR) is a widely recognized master regulator of cell migration, and uPAR88-92 is the minimal sequence required to induce cell motility. We previously showed that soluble formsofuPARelicitangiogenic responses throughtheiruPAR 88-92 chemotactic sequenceandthat the synthetic peptide SRSRY exerts similar effects. By a drug design approach, based on the conformational analysis of the uPAR88-92 sequence, we developed peptides (pERERY, RERY, and RERF) that potently inhibit signaling triggered by uPAR88-92. In this study, we present evidence that these peptides are endowed also with a clear-cut antiangiogenic activity, although to different extents. The most active, RERF, prevents tube formation by human endothelial cells exposed to SRSRY. RERF also inhibits VEGF-triggered endothelial cell migration and cord-like formation in a dose-dependentmanner, starting in the femtomolar range. RERF prevents F-actin polymerization, recruitment of αvβ3 integrin at focal adhesions, and αvβ3/VEGFR2 complex formation in endothelial cells exposed to VEGF. Atmolecular level, the inhibitory effect of RERF on VEGF signaling is shown by the decreased amount of phospho-FAK and phospho-Akt in VEGF-treated cells. In vivo, RERF prevents VEGF-dependent capillary sprouts originating from the host vessels that invaded angioreactors implanted in mice and neovascularization induced by subcorneal implantation of pellets containingVEGFin rabbits.Consistently, RERF reduced the growth and vascularization rate of tumors formed by HT1080 cells injected subcutaneously in the flanks of nude mice, indicating that RERF is a promising therapeutic agent for the control of diseases fuelled by excessive angiogenesis such as cancer.
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U2 - 10.1158/1535-7163.MCT-13-0077
DO - 10.1158/1535-7163.MCT-13-0077
M3 - Article
C2 - 23939376
AN - SCOPUS:84885640117
VL - 12
SP - 1981
EP - 1993
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
SN - 1535-7163
IS - 10
ER -