Abstract
Interfering with interactions of vascular endothelial growth factors (VEGFs) with their receptors (VEGFRs) effectively inhibits angiogenesis and tumor growth. We designed an antagonist peptide of VEGF-A and VEGF-B reproducing two discontinuous receptor binding regions of VEGF-B (loop 1 and loop3) covalently linked together by a receptor binding region of VEGF-A (loop3). The designed peptide (referred to as VGB4) was able to bind to both VEGFR1 and VEGFR2 on the Human Umbilical Vein Endothelial Cells (HUVECs) surface and inhibited VEGF-A driven proliferation, migration and tube formation in HUVECs through suppression of ERK1/2 and AKT phosphorylation. The whole-animal fluorescence imaging demonstrated that fluorescein isothiocyanate (FITC)-VGB4 accumulated in the mammary carcinoma tumors (MCTs). Administration of VGB4 led to the regression of 4T1 murine MCT growth through decreased expression of p-VEGFR1 and p-VEGFR2 and abrogation of ERK1/2 and AKT activation followed by considerable decrease of tumor cell proliferation (Ki67 expression) and angiogenesis (CD31 and CD34 expression), induction of apoptosis (increased p53 expression, TUNEL staining and decreased Bcl2 expression), and suppression of metastasis (increased E-cadherin and decreased N-cadherin, NF-κB and MMP-9 expression). These findings indicate that VGB4 may be applicable for antiangiogenic and antitumor therapy.
Highlights
Given uncontrolled cell proliferation of tumor tissue, new vascular growth occurs at high levels for further providing oxygen and nutrient supply for the fast-growing tumor cells[1]
The crystal structure of the complex between vascular endothelial growth factors (VEGFs)-B and the extracellular domain of VEGFR1 revealed that the β-hairpin fragment 79–93 and the segment 45–48 within α2-β3 loop in VEGF-B are in close proximity, forming an important binding interface with the second domain of VEGFR1 (VEGFR1 D2)[25]
Incubation with VGB4 led to a considerable reduction of fluorescent signals in a dose-dependent manner when compared to control and scr peptide (0.74 μM). These results show that VGB4 can bind to both VEGFR1 and VEGFR2 on the surface of endothelial cells and compete with antibodies that recognize the ectodomains of the receptors
Summary
Given uncontrolled cell proliferation of tumor tissue, new vascular growth occurs at high levels for further providing oxygen and nutrient supply for the fast-growing tumor cells[1]. Growth and metastasis[20], a linear peptide was rationally designed from α2-β3 loop (loop1) and β5-β6 loop (loop3) of VEGF-B as well as β5-β6 loop (loop3) of VEGF-A, according to their complex with VEGFR1 D2 and VEGFR2 D2. Based on in vitro and in vivo studies, VGB4 potently inhibited proliferation, migration and tube formation of human umbilical vein endothelial cells (HUVECs), as well as 4T1 mammary carcinoma tumor (MCT) angiogenesis, growth and metastasis. These results suggest that VGB4 is a potential candidate for future clinical investigations
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