Brucine Suppresses Vasculogenic Mimicry in Human Triple-Negative Breast Cancer Cell Line MDA-MB-231
Brucine Suppresses Vasculogenic Mimicry in Human Triple-Negative Breast Cancer Cell Line MDA-MB-231
复制标题
马钱子碱抑制人三阴性乳腺癌细胞系 MDA-MB-231 中的血管生成拟态
DOI：
10.1155/2019/6543230
复制
发表时间：
2019-01-01
影响因子：
--
通讯作者：
Li, Ping
中科院分区：
文献类型：
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作者：
Xu, Meng-Ran;Wei, Peng-Fei;Li, Ping
血管生成拟态（vasculogenic mimicry，VM）是一种由侵袭性肿瘤细胞形成的非内皮依赖性管状结构，可模拟正常的肿瘤血管，保证肿瘤的血液供应，与恶性肿瘤的增殖、侵袭、转移和预后不良密切相关，是肿瘤抗血管生成治疗耐药的主要障碍。因此，迫切需要寻找抑制肿瘤VM形成的方法，这对提高肿瘤治疗水平具有重要的现实意义。马钱子碱是从马钱子种子中提取的传统中草药。（马钱科）在多种癌症模型中表现出抗肿瘤活性。本研究旨在探讨马钱子碱对血管生成拟态的影响及其机制。我们证明，在三阴性乳腺癌细胞系MDA-MB-231中，马钱子碱在较高浓度下诱导细胞增殖的剂量依赖性抑制作用沿着凋亡诱导。进一步的研究表明马钱子碱抑制细胞的迁移和侵袭，并呈剂量依赖性。我们的研究结果首次表明，马钱子碱可以破坏F-肌动蛋白细胞骨架和微管结构，从而损害侵袭性肿瘤的标志，如迁移，侵袭，并保持抑制血管生成拟态的可能性。进一步证实了马钱子碱对血管生成拟态的抑制作用。结果表明，马钱子碱显着抑制血管生成拟态管的形成与剂量依赖性的影响表明，小管的数量，交叉，和平均长度的小管的变化。初步探讨了马钱子碱抑制血管生成拟态的分子机制。马钱子碱抑制血管生成拟态可能是通过下调促红细胞生成素的肝细胞癌A2和基质金属蛋白酶-2和金属蛋白酶-9。
Vasculogenic mimicry (VM) with the pattern of endothelial independent tubular structure formation lined by aggressive tumor cells mimics regular tumor blood vessels to ensure robust blood supply and correlates with the proliferation, invasion, metastasis, and poor prognosis of malignant tumors, which was demonstrated to be a major obstacle for resistance to antiangiogenesis therapy. Therefore, it is urgent to discover methods to abrogate the VM formation of tumors, which possesses important practical significance for improving tumor therapy. Brucine is a traditional medicinal herb extracted from seeds of Strychnos nux-vomica L. (Loganiaceae) exhibiting antitumor activity in a variety of cancer models. In the present study, the effect of brucine on vasculogenic mimicry and the related mechanism are to be investigated. We demonstrated that, in a triple-negative breast cancer cell line MDA-MB-231, brucine induced a dose-dependent inhibitory effect on cell proliferation along with apoptosis induction at higher concentrations. The further study showed that brucine inhibited cell migration and invasion with a dose-dependent manner. Our results for the first time indicated that brucine could disrupt F-actin cytoskeleton and microtubule structure, thereby impairing hallmarks of aggressive tumors, like migration, invasion, and holding a possibility of suppressing vasculogenic mimicry. Hence, the inhibitory effect of brucine on vasculogenic mimicry was further verified. The results illustrated that brucine significantly suppressed vasculogenic mimicry tube formation with a dose-dependent effect indicated by the change of the number of tubules, intersections, and mean length of tubules. The in-depth molecular mechanism of vasculogenic mimicry suppression induced by brucine was finally suggested. It was demonstrated that brucine inhibited vasculogenic mimicry which might be through the downregulation of erythropoietin-producing hepatocellular carcinoma-A2 and matrix metalloproteinase-2 and metalloproteinase-9.