Emodin Suppresses Maintenance of Stemness by Augmenting Proteosomal Degradation of Epidermal Growth Factor Receptor/Epidermal Growth Factor Receptor Variant III in Glioma Stem Cells
Emodin Suppresses Maintenance of Stemness by Augmenting Proteosomal Degradation of Epidermal Growth Factor Receptor/Epidermal Growth Factor Receptor Variant III in Glioma Stem Cells
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DOI：
10.1089/scd.2014.0210
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发表时间：
2015-02-01
影响因子：
4
通讯作者：
Park, Myung-Jin
中科院分区：
文献类型：
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作者：
Kim, Jeongyub;Lee, Jong-Seon;Park, Myung-Jin
越来越多的证据表明，大多数实体瘤中具有干细胞样特征的细胞亚群是侵袭性癌细胞恶性程度的原因，靶向这些细胞可能是降低治疗后肿瘤复发风险的良好治疗策略。在这里，我们研究了大黄素（1，3，8-三羟基-6-甲基蒽醌）的作用，大黄的根和根茎的活性成分，具有多种生物活性，包括抗肿瘤作用，对原代培养的胶质瘤干细胞（GSCs）。神经球形成、有限稀释和软琼脂克隆形成试验证明大黄素在体外抑制GSC的自我更新活性。大黄素通过抑制Notch胞内结构域、非磷酸化β-连环蛋白和磷酸化STAT 3蛋白的表达来抑制干性的维持。此外，大黄素治疗部分诱导细胞凋亡，降低细胞侵袭力，并致敏GSC电离辐射。有趣的是，大黄素通过干扰EGFR/EGFRvIII与热休克蛋白90的结合，诱导表皮生长因子受体（EGFR）/EGFR变体III（EGFRvIII）的蛋白质体降解，从而抑制干性途径。基于这些数据，我们建议大黄素可以被认为是一种有效的治疗佐剂，靶向GSC。
There is a growing body of evidence that small subpopulations of cells with stem cell-like characteristics within most solid tumors are responsible for the malignancy of aggressive cancer cells and that targeting these cells might be a good therapeutic strategy to reduce the risk of tumor relapse after therapy. Here, we examined the effects of emodin (1,3,8-trihydroxy-6-methylanthraquinone), an active component of the root and rhizome of Rheum palmatum that has several biological activities, including antitumor effects, on primary cultured glioma stem cells (GSCs). Emodin inhibited the self-renewal activity of GSCs in vitro as evidenced by neurosphere formation, limiting dilution, and soft agar clonogenic assays. Emodin inhibited the maintenance of stemness by suppressing the expression of Notch intracellular domain, nonphosphorylated beta-catenin, and phosphorylated STAT3 proteins. In addition, treatment with emodin partially induced apoptosis, reduced cell invasiveness, and sensitized GSCs to ionizing radiation. Intriguingly, emodin induced proteosomal degradation of epidermal growth factor receptor (EGFR)/EGFR variant III (EGFRvIII) by interfering with the association of EGFR/EGFRvIII with heat shock protein 90, resulting in the suppression of stemness pathways. Based on these data, we propose that emodin could be considered as a potent therapeutic adjuvant that targets GSCs.