Casein Kinase 1 Epsilon Regulates Glioblastoma Cell Survival.
Casein Kinase 1 Epsilon Regulates Glioblastoma Cell Survival.
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DOI：
10.1038/s41598-018-31864-x
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发表时间：
2018-09-11
影响因子：
4.6
通讯作者：
Sheng Z
中科院分区：
文献类型：
--
作者：
Varghese RT;Young S;Pham L;Liang Y;Pridham KJ;Guo S;Murphy S;Kelly DF;Sheng Z
胶质母细胞瘤是最常见的恶性脑癌，预后很差。胶质母细胞瘤治疗的困难主要归因于缺乏有效的治疗靶点。在我们以前的工作中，我们确定了酪蛋白激酶1 ε（CK 1 ε，也称为CSNK 1 E）作为胶质母细胞瘤的潜在生存因子。然而，CK 1 ε如何控制细胞存活仍然难以捉摸，靶向CK 1 ε是否是胶质母细胞瘤的可能治疗方法需要进一步研究。在此我们报道了CK 1 ε在胶质母细胞瘤中的表达水平在6种CK 1亚型中最高，并在高级别胶质瘤中富集，但在胶质细胞中不表达。CK 1 ε的缺失显著抑制胶质母细胞瘤细胞的生长和胶质母细胞瘤干细胞的自我更新，而对星形胶质细胞的影响有限。CK 1 ε剥夺激活β-catenin并诱导细胞凋亡，这被β-catenin的敲低进一步抵消。CK 1 ε抑制剂IC 261（而非PF-4800567）激活β-连环蛋白并阻断胶质母细胞瘤细胞和胶质母细胞瘤干细胞的生长。相应地，IC 261在小鼠中引起人胶质母细胞瘤异种移植物的稳健生长抑制。总之，我们的结果表明，CK 1 ε通过β-连环蛋白信号传导调节胶质母细胞瘤细胞和胶质母细胞瘤干细胞的存活，强调了靶向CK 1 ε作为胶质母细胞瘤有效治疗的重要性。
Glioblastoma is the most common malignant brain cancer with a dismal prognosis. The difficulty in treating glioblastoma is largely attributed to the lack of effective therapeutic targets. In our previous work, we identified casein kinase 1 ε (CK1ε, also known as CSNK1E) as a potential survival factor in glioblastoma. However, how CK1ε controls cell survival remains elusive and whether targeting CK1ε is a possible treatment for glioblastoma requires further investigation. Here we report that CK1ε was expressed at the highest level among six CK1 isoforms in glioblastoma and enriched in high-grade glioma, but not glia cells. Depletion of CK1ε remarkably inhibited the growth of glioblastoma cells and suppressed self-renewal of glioblastoma stem cells, while having limited effect on astrocytes. CK1ε deprivation activated β-catenin and induced apoptosis, which was further counteracted by knockdown of β-catenin. The CK1ε inhibitor IC261, but not PF-4800567, activated β-catenin and blocked the growth of glioblastoma cells and glioblastoma stem cells. Congruently, IC261 elicited a robust growth inhibition of human glioblastoma xenografts in mice. Together, our results demonstrate that CK1ε regulates the survival of glioblastoma cells and glioblastoma stem cells through β-catenin signaling, underscoring the importance of targeting CK1ε as an effective treatment for glioblastoma.
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影响因子：
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