Dual blockade of VEGFR1 and VEGFR2 by a novel peptide abrogates VEGF-driven angiogenesis,tumor growth,and metastasis through PI3K/AKT and MAPK/ERK1/2 pathway |
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Authors: | Afsaneh Sadremomtaz Kamran Mansouri Golnaz Alemzadeh Majid Safa Ahmadreza Esmaeili Rastaghi S. Mohsen Asghari |
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Affiliation: | 1. Department of Biology, Faculty of Sciences, University of Guilan, Rasht, Iran;2. Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran;3. Department of Anesthesiology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA;4. Ronald Reagan UCLA Medical Center, Santa Monica, USA;5. Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran;6. Department of Hematology, Faculty of Medical Sciences, Tehran, Iran;7. Department of Parasitology, Pasteur Institute of Iran, Tehran, Iran |
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Abstract: | BackgroundNeutralization of vascular endothelial growth factor receptor 1 (VEGFR1) and/or VEGFR2 is a widely used means of inhibiting tumor angiogenesis.MethodsBased on the complex X-ray structures of VEGFA/VEGFR1, VEGFA/VEGFR2, and VEGFB/VEGFR1, a peptide (referred to as VGB) was designed to simultaneously bind to VEGFR1 and VEGFR2, and binding, antiangiogenic and antitumor properties of the peptide was investigated in vitro.ResultsVGB bound to both VEGFR1 and VEGFR2 in human umbilical vein endothelial cells (HUVECs) and 4?T1 mammary carcinoma tumor (MCT) cells, and inhibited the proliferation of HUVE, 4?T1 MCT, and U87 glioblastoma cells. Through abrogation of AKT and ERK1/2 phosphorylation, VEGFA-stimulated proliferation, migration, and two- and three-dimensional tube formation in HUVECs were inhibited more potently by VGB than by bevacizumab. In a murine 4?T1 MCT model, VGB strongly inhibited tumor growth without causing weight loss, accompanied by inhibition of AKT and ERK1/2 phosphorylation, a significant decrease in tumor cell proliferation (Ki-67 expression), angiogenesis (CD31 and CD34 expression), an increase in apoptosis index (increased TUNEL staining and p53 expression and decreased Bcl-2 expression), and the suppression of systematic spreading of the tumor (reduced NF-κB and MMP-9 and increased E-cadherin expression).ConclusionThe dual specificity of VGB for VEGFR1 and VEGFR2, through which the PI3K/AKT and MAPK/ERK1/2 signaling pathways can be abrogated and, subsequently, angiogenesis, tumor growth, and metastasis are inhibited.General significanceThis study demonstrated that simultaneous blockade of VEGFR1 and VEGFR2 downstream cascades is an effective means for treatment of various angiogenic disorders, especially cancer. |
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Keywords: | VEGFR1 VEGFR2 Peptide design Angiogenesis Tumor growth |
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