Acyclic retinoid inhibits angiogenesis by suppressing the MAPK pathway
Acyclic retinoid inhibits angiogenesis by suppressing the MAPK pathway
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DOI：
10.1038/labinvest.2009.110
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发表时间：
2010-01-01
影响因子：
5
通讯作者：
Kojima, Soichi
中科院分区：
文献类型：
--
作者：
Komi, Yusuke;Sogabe, Yukihisa;Kojima, Soichi
无环类维甲酸（ACR）目前正在临床试验中，通过其诱导早期肝癌细胞凋亡的能力，作为抑制肝细胞癌（HCC）复发的药物。ACR在体内也有抗癌作用，尽管它对成熟的HCC细胞表现出较弱的诱导凋亡活性，这表明存在另一种作用机制。在本研究中，我们研究了ACR的抗血管生成活性。ACR抑制鸡绒毛膜尿囊膜（CAM）血管生成的作用与全反式维甲酸（atRA）相似。虽然同时加入血管生成素-1可以部分恢复atRA对血管生成的抑制，但在相同条件下，ACR对血管生成的抑制完全不能恢复。相反，尽管同时加入血管内皮生长因子（VEGF）可以部分逆转ACR对血管生成的抑制作用，但在相同条件下，atRA对血管生成的抑制作用不受影响。这些结果表明ACR和atRA抑制血管生成的机制是不同的。ACR选择性地抑制VEGF受体2 （VEGFR2）和细胞外信号调节激酶（ERK）的磷酸化，而不改变它们的蛋白表达水平，抑制内皮细胞的生长、迁移和管的形成。ACR对ERK磷酸化、内皮生长、迁移、管形成和血管生成的抑制作用，通过过表达组成型活性丝裂原活化蛋白激酶（MAPK）得以恢复。最后，在异种移植的CAM模型中，ACR而不是atRA抑制hcc诱导的血管生成。这些结果描述了ACR通过强烈抑制VEGFR2 MAPK通路作为抗血管生成的新活性。实验室调查（2010）90,52-60；doi: 10.1038 / labinvest.2009.110;2009年10月19日在线发布
Acyclic retinoid (ACR) is currently under clinical trial as an agent to suppress the recurrence of hepatocellular carcinoma (HCC) through its ability to induce apoptosis in premature HCC cells. ACR has an anticancer effect in vivo as well, although it shows weak apoptosis-inducing activity against mature HCC cells, suggesting the existence of an additional action mechanism. In this study, we investigated the antiangiogenic activity of ACR. ACR inhibited angiogenesis within chicken chorioallantoic membrane (CAM) in as similar a manner as all-trans retinoic acid (atRA). Although suppression of angiogenesis by atRA was partially rescued by the simultaneous addition of angiopoietin-1, suppression of angiogenesis by ACR was not rescued under the same condition at all. Conversely, although suppression of angiogenesis by ACR was partially inverted by the simultaneous addition of vascular endothelial growth factor (VEGF), suppression of angiogenesis by atRA was not affected under the same condition. These results suggested that mechanisms underlying the suppression of angiogenesis by ACR and atRA were different. ACR selectively inhibited the phosphorylation of VEGF receptor 2 (VEGFR2) and of extracellular signal-regulated kinase (ERK) without changing their protein expression levels, and inhibited endothelial cell growth, migration, and tube formation. The inhibition of the phosphorylation of ERK, endothelial growth, migration, tube formation, and angiogenesis by ACR was rescued by the overexpression of constitutively active mitogen-activated protein kinase (MAPK). Finally, ACR, but not atRA, inhibited HCC-induced angiogenesis in a xenografted CAM model. These results delineate the novel activity of ACR as an antiangiogenic through a strong inhibition of the VEGFR2 MAPK pathway. Laboratory Investigation (2010) 90, 52-60; doi:10.1038/labinvest.2009.110; published online 19 October 2009