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
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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DOI：
10.1016/j.bbagen.2018.08.013
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发表时间：
2018-12-01
影响因子：
3
通讯作者：
Asghari, S. Mohsen
中科院分区：
文献类型：
--
作者：
Sadremomtaz, Afsaneh;Mansouri, Kamran;Asghari, S. Mohsen
背景资料：中和血管内皮生长因子受体1（VEGFR 1）和/或VEGFR 2是抑制肿瘤血管生成的广泛使用的手段。基于VEGFA/VEGFR 1、VEGFA/VEGFR 2和VEGFB/VEGFR 1的复杂X射线结构，（称为VGB）被设计为同时结合VEGFR 1和VEGFR 2，体外抗血管生成和抗肿瘤活性的研究。VGB可与人脐静脉内皮细胞（HUVECs）和4 T1乳腺癌肿瘤细胞（MCT）中的VEGFR 1和VEGFR 2结合，并抑制HUVE的增殖，4 T1 MCT和U87胶质母细胞瘤细胞。通过废除AKT和ERIC 1/2磷酸化，VGB比贝伐单抗更有效地抑制HUVEC中VEGF刺激的增殖、迁移以及二维和三维管形成。在小鼠4 T1 MCT模型中，VGB强烈抑制肿瘤生长而不引起体重减轻，同时抑制AKT和ERK 112磷酸化，显著降低肿瘤细胞增殖（Ki-67表达），血管生成（CD 31和CD 34表达），凋亡指数增加（增加TUNEL染色和p53表达，降低Bc 1 -2表达），并抑制肿瘤的系统性扩散（减少NF-κ B和MMP-9的表达，增加E-钙粘蛋白的表达）。VGB对VEGFR 1和VEGFR 2的双重特异性，通过VGB可以消除PI 3 K/AKT和MAPK/ERK 1/2信号通路，随后，血管生成，肿瘤生长，一般意义：本研究表明，同时阻断VEGFR 1和VEGFR 2下游级联反应是治疗各种血管生成疾病，特别是癌症的有效手段。
Background: Neutralization of vascular endothelial growth factor receptor 1 (VEGFR1) and/or VEGFR2 is a widely used means of inhibiting tumor angiogenesis.Methods: Based 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.Results: VGB 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 ERICl/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 4T1 MCT model, VGB strongly inhibited tumor growth without causing weight loss, accompanied by inhibition of AKT and ERK112 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 Bc1-2 expression), and the suppression of systematic spreading of the tumor (reduced NF-kappa B and MMP-9 and increased E-cadherin expression).Conclusion: The 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 significance: This study demonstrated that simultaneous blockade of VEGFR1 and VEGFR2 downstream cascades is an effective means for treatment of various angiogenic disorders, especially cancer.