Combretastatin A-1 phosphate, a microtubule inhibitor, acts on both hepatocellular carcinoma cells and tumor-associated macrophages by inhibiting the Wnt/β-catenin pathway
Combretastatin A-1 phosphate, a microtubule inhibitor, acts on both hepatocellular carcinoma cells and tumor-associated macrophages by inhibiting the Wnt/β-catenin pathway
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Combretastatin A-1 磷酸盐是一种微管抑制剂，通过抑制 Wnt/β-catenin 通路作用于肝细胞癌细胞和肿瘤相关巨噬细胞
DOI：
10.1016/j.canlet.2016.06.020
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发表时间：
2016-09-28
期刊：
影响因子：
9.7
通讯作者：
Yang, Yong
中科院分区：
文献类型：
--
作者：
Mao, Jie;Wang, Duowei;Yang, Yong
考布他汀A-1磷酸盐（CA 1 P）是一种微管聚合抑制剂，可与微管蛋白的秋水仙素结合位点结合。我们证明了CA 1 P在体外和体内对肝细胞癌（HCC）具有突出的抗癌活性。通过荧光染色和蛋白质印迹（WB）检测，CM 1 P诱导HepG 2细胞活性氧（ROS）积累和凋亡，并下调Mcl-1的表达。其他研究表明，CA 1 P诱导微管解聚介导的AKT失活，导致GSK-3 β激活，Wnt/β-连环蛋白途径抑制和Mcl-1下调。GSK-3 β特异性抑制剂可抑制CA 1 P诱导的HepG 2细胞凋亡。此外，肝细胞癌小鼠模型的免疫组织化学研究表明，CA 1 P对肿瘤相关巨噬细胞（TAMS）具有活性。CA 1 P通过与HepG 2细胞观察到的相同机制在体外诱导TAM凋亡，并且在体内消除肿瘤微环境（TME）中的TAMS。在TME中，TGF-β和TNF-α的表达也发生了变化。巨噬细胞的过继转移部分地挽救了被CA 1 P抑制的肿瘤生长。这些结果表明，CA 1 P具有很大的潜力，影响癌细胞和微环境，我们的研究结果将加速CA 1 P在肝癌治疗中的临床应用。(C)2016爱思唯尔爱尔兰有限公司版权所有。
Combretastatin A-1 phosphate (CA1P) is a microtubule polymerization inhibitor that binds to the colchicine-binding site of tubulin. We demonstrated that CA1P has outstanding anti-cancer activity against hepatocellular carcinoma (HCC) in vitro and in vivo. As determined by fluorescence staining and western blots (WBs), CM1P induced reactive oxygen species (ROS) accumulation and apoptosis in HepG2 cells with a down-regulation of Mcl-1. Additional studies indicated that CA1P induced microtubule depolymerization-mediated AKT inactivation, which resulted in GSK-3 beta activation, Wnt/beta-Catenin pathway inhibition, and Mcl-1 down-regulation. The induction of HepG2 cell apoptosis by CA1P was prevented by a GSK-3 beta-specific inhibitor. Furthermore, immunohistochemistry studies on hepatocellular carcinoma mouse models showed that CA1P had activity against tumor-associated macrophages (TAMS). CA1P induced TAM apoptosis in vitro through the same mechanism observed with HepG2 cells, and it eliminated TAMS in the tumor microenvironment (TME) in vivo. In TME, the expression of TGF-beta and TNF-alpha was also altered. The adoptive transfer of macrophages partly rescued the growth of tumor inhibited by CA1P. These findings indicate that CA1P has great potential to impact both cancer cells and the microenvironment, and our results should accelerate the application of CA1P for HCC therapy in clinic. (C) 2016 Elsevier Ireland Ltd. All rights reserved.