A novel angiogenesis inhibitor impairs lovo cell survival via targeting against human VEGFR and its signaling pathway of phosphorylation.
A novel angiogenesis inhibitor impairs lovo cell survival via targeting against human VEGFR and its signaling pathway of phosphorylation.
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一种新型血管生成抑制剂通过针对人 VEGFR 及其磷酸化信号通路损害 Lovo 细胞存活
DOI：
10.1038/cddis.2012.145
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发表时间：
2012-10-11
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
结直肠癌代表第四常见的恶性肿瘤，并且构成其他疾病中显著发病率和死亡率的主要原因。然而，化学疗法仍在发展中。血管生成在结肠癌的发展中起重要作用。我们开发了HMQ 18 -22（塔斯品碱的新型类似物），目的是靶向血管生成。我们发现HMQ 18 -22显著降低鸡胚绒毛尿囊膜（CAM）和小鼠结肠组织的血管生成，并抑制细胞迁移和管形成。通过AlphaScreen P-VEGFR检测验证HMQ 18 -22与VEGFR 2的相互作用，通过VEGF Phospho Antibody Array筛选血管生成靶点，并在lovo细胞中通过western blot和RNAi验证靶点。我们发现HMQ 18 -22可降低VEGFR 2（Tyr 1214）、VEGFR 1（Tyr 1333）、Akt（Tyr 326）、蛋白激酶Cα（PKCα）（Tyr 657）和磷脂酶-C γ-1（PLCγ-1）（Tyr 771）的磷酸化。最重要的是，HMQ 18 -22可抑制lovo细胞增殖和无胸腺小鼠人结肠肿瘤异种移植模型中的肿瘤生长。HMQ 18 -22对VEGFR 2、VEGFR 1、Akt、PKCα和PLCγ-1基因敲减的lovo细胞增殖抑制作用较正常细胞明显减弱。这些结果表明，HMQ 18 -22是一种新的血管生成抑制剂，可以成为结肠癌干预的有用的治疗候选物。
Colorectal cancer represents the fourth commonest malignancy, and constitutes a major cause of significant morbidity and mortality among other diseases. However, the chemical therapy is still under development. Angiogenesis plays an important role in colon cancer development. We developed HMQ18–22 (a novel analog of taspine) with the aim to target angiogenesis. We found that HMQ18–22 significantly reduced angiogenesis of chicken chorioallantoic membrane (CAM) and mouse colon tissue, and inhibited cell migration and tube formation as well. Then, we verified the interaction between HMQ18–22 and VEGFR2 by AlphaScreen P-VEGFR assay, screened the targets on angiogenesis by VEGF Phospho Antibody Array, validated the target by western blot and RNAi in lovo cells. We found HMQ18–22 could decrease phosphorylation of VEGFR2 (Tyr 1214), VEGFR1 (Tyr 1333), Akt (Tyr 326), protein kinase Cα (PKCα)(Tyr 657) and phospholipase-Cγ-1 (PLCγ-1)(Tyr 771). Most importantly, HMQ18–22 inhibited proliferation of lovo cell and tumor growth in a human colon tumor xenografted model of athymic mice. Compared with normal lovo cells proliferation, the inhibition on proliferation of knockdown cells (VEGFR2, VEGFR1, Akt, PKCα and PLCγ-1) by HMQ18–22 decreased. These results suggested that HMQ18–22 is a novel angiogenesis inhibitor and can be a useful therapeutic candidate for colon cancer intervention.
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影响因子：
11.2
作者：
Adams LS;Phung S;Yee N;Seeram NP;Li L;Chen S
通讯作者：
Chen S
影响因子：
5.8
作者：
Berra, E;Milanini, J;Pouysségur, J
通讯作者：
Pouysségur, J
影响因子：
8
作者：
Piccolo, E;Innominato, PF;Falasca, M
通讯作者：
Falasca, M
影响因子：
44.1
作者：
Kim, Hyung-Jin;Oh, Gi-Su;Park, Raekil
通讯作者：
Park, Raekil
影响因子：
9.7
作者：
Huh, Jeong-Eun;Baek, Yong-Hyeon;Lee, Jae-Dong
通讯作者：
Lee, Jae-Dong