Glycogen synthase kinases-3β controls differentiation of malignant glioma cells
Glycogen synthase kinases-3β controls differentiation of malignant glioma cells
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DOI：
10.1002/ijc.25020
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发表时间：
2010-09-15
影响因子：
6.4
通讯作者：
Yan, Guangmei
中科院分区：
文献类型：
--
作者：
Li, Yan;Lu, Huimin;Yan, Guangmei
恶性神经胶质瘤持续作为成人发病率和死亡率的主要疾病。分化治疗已成为一种有前途的候选治疗方式。然而，相关机制尚不清楚。在这里，我们发现，在敏感的 C6 和 U87-MG 恶性胶质瘤细胞中，在霍乱毒素诱导的分化过程中，糖原合酶激酶 3 beta (GSK-3 beta) 高度表达并被激活，而 GSK-3 α 活性保持稳定。 GSK-3 β 抑制剂或小干扰 RNA 抑制敏感 C6 细胞的诱导分化。相反，在耐药性 U251 神经胶质瘤细胞中过度表达人 GSK-3 beta (pcDNA3-GSK-3 beta-S9A) 突变体的组成型活性形式可恢复其分化能力。此外，GSK-3 beta 会触发细胞周期蛋白 D1 核输出和随后的降解，这对于 C6 和 U251 神经胶质瘤细胞的分化是必需的。对人类神经胶质瘤组织的分析进一步揭示了活性 GSK-3 beta 的过度表达。这些发现表明 GSK-3 β 是分化命运决定因素，并为 GSK-3 β 调节神经胶质瘤中细胞周期蛋白 D1 降解和细胞分化的机制提供了新的线索。
Malignant gliomas persist as a major disease of morbidity and mortality in adult. Differentiation therapy has emerged as a promising candidate modality. However, the mechanism related is unknown. Here, we show that glycogen synthase kinase-3 beta (GSK-3 beta) is highly expressed and activated during the cholera toxin-induced differentiation in sensitive C6 and U87-MG malignant glioma cells, whereas the GSK-3 alpha activity remains stable. GSK-3 beta inhibitors or small interfering RNA suppress the induced-differentiation in sensitive C6 cells. Conversely, overexpression of a constitutively active form of human GSK-3 beta (pcDNA3-GSK-3 beta-S9A) mutant in resistant U251 glioma cells restores their differentiation capabilities. In addition, GSK-3 beta triggers cyclin D1 nuclear export and subsequent degradation, which is necessary for differentiation in C6 and U251 glioma cells. Analysis of human glioma tissues further revealed overexpression of active GSK-3 beta. These findings suggest that GSK-3 beta is a differentiation fate determinant, and shed new lights on the mechanism by which GSK-3 beta regulates cyclin D1 degradation and cellular differentiation in gliomas.