Cordycepin regulates GSK-3β/β-catenin signaling in human leukemia cells.
Cordycepin regulates GSK-3β/β-catenin signaling in human leukemia cells.
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DOI：
10.1371/journal.pone.0076320
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Liou JY
中科院分区：
文献类型：
--
作者：
Ko BS;Lu YJ;Yao WL;Liu TA;Tzean SS;Shen TL;Liou JY
白血病干细胞（LSC）是白血病发生和维持的无限细胞来源。 Wnt/β-catenin 通路的激活是 LSC 生存和发育所必需的。因此，靶向β-catenin被认为是治疗白血病的一种治疗策略。本研究的目的是探讨传统药物冬虫夏草的活性成分虫草素是否调节白血病细胞中的β-连环蛋白表达。在这项研究中，我们发现虫草素以剂量依赖性方式显着抑制所有恶性癌细胞的细胞增殖，包括U937、K562、A549、HepG2、SK-Hep1和MCF7。然而，虫草素降低了 U937、K562 和 THP1 白血病细胞中的 β-连环蛋白水平，而对其他实体癌细胞没有影响。此外，在软琼脂测定中，虫草素处理显着抑制了白血病集落形成。虫草素增强白血病细胞中蛋白酶体依赖性降解并抑制 β-连环蛋白的核转位。通过添加 GSK-3β 药理学抑制剂可以恢复虫草素降低的 β-连环蛋白稳定性，表明虫草素抑制的 β-连环蛋白稳定性是通过 GSK-3β 的激活介导的。此外，虫草素消除了 Wnt3a 诱导的 β-连环蛋白在白血病细胞中的作用。此外，虫草素受损的 β-catenin 受 Akt 激活调节，但不受 AMPK 或 mTOR 信号通路的显着影响。我们的研究结果首次表明，虫草素选择性降低白血病中β-连环蛋白的稳定性，但不会降低其他实体瘤细胞中的β-连环蛋白稳定性。这种抑制作用是通过调节 GSK-3β 介导的。虫草素与其他治疗方法的协同组合应作为通过消除 LSC 来根除白血病的新策略。
Leukemia stem cells (LSCs) are a limitless cell source for the initiation and maintenance of leukemia. Activation of the Wnt/β-catenin pathway is required for the survival and development of LSCs. Therefore, targeting β-catenin is considered a therapeutic strategy for the treatment of leukemia. The goal of this study was to explore whether cordycepin, an active component of the traditional medicine Cordyceps sinensis, regulates β-catenin expression in leukemia cells. In this study, we found that cordycepin significantly suppressed cell proliferation in all malignant cancer cells, including U937, K562, A549, HepG2, SK-Hep1 and MCF7 in a dose-dependent manner. However, cordycepin reduced β-catenin levels in U937, K562 and THP1 leukemia cells and had no effect on other solid cancer cells. In addition, treatment with cordycepin significantly suppressed leukemia colony formation in soft agar assay. Cordycepin enhanced proteasome-dependent degradation and inhibited nuclear translocation of β-catenin in leukemia cells. Cordycepin-reduced β-catenin stability was restored by the addition of a pharmacological inhibitor of GSK-3β, indicating that cordycepin-suppressed β-catenin stability is mediated by the activation of GSK-3β. Furthermore, cordycepin abolished the effect of Wnt3a-induced β-catenin in leukemia cells. In addition, cordycepin-impaired β-catenin is regulated by Akt activation but is not significantly influenced by AMPK or mTOR signal pathways. Our findings show for the first time that codycepin selectively reduces β-catenin stability in leukemia but not in other solid tumor cells. This suppressive effect is mediated by regulating GSK-3β. A synergistic combination of cordycepin with other treatments should be used as a novel strategy to eradicate leukemia via elimination of LSCs.
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