Shikonin inhibits triple-negative breast cancer-cell metastasis by reversing the epithelial-to-mesenchymal transition via glycogen synthase kinase 3β-regulated suppression of β-catenin signaling
Shikonin inhibits triple-negative breast cancer-cell metastasis by reversing the epithelial-to-mesenchymal transition via glycogen synthase kinase 3β-regulated suppression of β-catenin signaling
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DOI：
10.1016/j.bcp.2019.05.001
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发表时间：
2019-08-01
影响因子：
5.8
通讯作者：
Shen, Xiang-chun
中科院分区：
文献类型：
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作者：
Chen, Yan;Chen, Zong-yue;Shen, Xiang-chun
三阴性乳腺癌（TNBC）的特征在于转移增加、存活率低和对治疗的反应差。尽管已经研究了许多用于治疗TNBC的特异性和有效的药剂，但有希望的治疗选择仍然难以捉摸。本文对紫草的三种主要成分进行了抑菌活性筛选。et Zucc（紫草素、乙酰紫草素和β，β-二甲基丙烯酰紫草素）对TNBC细胞的作用。结果显示，紫草素有效地降低TNBC MDA-MB-231和4 T1细胞的活力，但对正常乳腺上皮MCF-12 A细胞显示出较小的细胞毒性。此外，紫草素逆转了MDA-MB-231和4 T1细胞中的上皮向间质转化（EMT）。紫草素抑制细胞迁移和侵袭，上调E-钙粘蛋白水平，下调N-钙粘蛋白，波形蛋白和蜗牛水平，并重组细胞骨架蛋白F-肌动蛋白和波形蛋白。紫草素通过减弱β-连环蛋白表达、核积累、与T细胞因子共有寡核苷酸的结合以及其靶向EMT相关基因的转录来抑制β-连环蛋白信号传导的活化，从而逆转EMT。此外，紫草素上调糖原合成酶激酶3 β（GSK-3 β）水平，导致磷酸化增强和β-连环蛋白水平降低。此外，紫草素给药显著抑制NOD/SCID小鼠中MDA-MB-231细胞的肺转移，伴有低全身毒性。组织学分析证实，紫草素升高了肺转移灶中E-钙粘蛋白、磷酸化β-连环蛋白和GSK-3 β的水平，降低了波形蛋白和β-连环蛋白的水平。这些结果表明，紫草素通过GSK-3 β调节的β-连环蛋白信号转导抑制靶向EMT而有效抑制TNBC转移，这突出了紫草素作为针对TNBC的新型抗癌治疗剂的潜在候选物的重要性。
Triple-negative breast cancer (TNBC) is characterized by elevated metastasis, low survival, and poor response to therapy. Although many specific and effective agents for treating TNBC have been investigated, promising therapeutic options remain elusive. Here, we screened the inhibitory activities of three main components of Lithospermum erythrorhizon Sieb. et Zucc (shikonin, acetylshikonin, and beta,beta-dimethylacrylshikonin) on TNBC cells. The results revealed that shikonin potently decreased the viabilities of TNBC MDA-MB-231 and 4T1 cells but showed less cytotoxicity to normal mammary epithelial MCF-12A cells. Additionally, shikonin reversed the epithelial-to-mesenchymal transition (EMT) in MDA-MB-231 and 4T1 cells. Shikonin depressed cell migration and invasion, upregulated E-cadherin levels, downregulated N-cadherin, vimentin, and Snail levels, and re-organized the cytoskeletal proteins F-actin and vimentin. Shikonin reversed EMT by inhibiting activation of beta-catenin signaling through attenuating beta-catenin expression, nuclear accumulation, binding to T-cell factor consensus oligos, and transcription of its targeted EMT-related genes. Moreover, shikonin upregulated glycogen synthase kinase 3 beta (GSK-3 beta) levels, leading to enhanced phosphorylation and decreased levels of beta-catenin. Furthermore, shikonin administration significantly inhibited lung metastasis of MDA-MB-231 cells in NOD/SCID mice accompanied by low systemic toxicity. Histological analysis confirmed that shikonin elevated levels of E-cadherin, phosphorylated beta-catenin, and GSK-3 beta, and decreased levels of vimentin and beta-catenin in pulmonary metastatic foci. These results indicated that shikonin potently inhibits TNBC metastasis by targeting the EMT via GSK-3 beta-regulated suppression of beta-catenin signaling, which highlights the importance of shikonin as a potential candidate for novel anticancer therapeutics against TNBC.