文章：

Abemaciclib通过靶向GSK3β介导的CD44和TCF7L2转录调控损害胶质母细胞瘤球体形成

Abemaciclib impairs glioblastoma sphere formation by targeting the GSK3β-mediated transcriptional regulation of CD44 and TCF7L2 

原文发布日期：2025-08-14 

英文摘要：

Glioblastoma multiforme (GBM) is an aggressive brain tumor partly driven by cancer stem cells (CSCs). Abemaciclib demonstrates the potential for treating GBM, although its mechanisms beyond RB phosphorylation are not fully understood. This study reveals that Abemaciclib diminishes GBM sphere formation by influencing EMT pathways via GSK3β-mediated regulation of CD44 and TCF7L2. Treatment with Abemaciclib significantly hindered sphere formation in GBM cells, and transcriptomic analysis indicated EMT pathways suppression. Mechanistically, Abemaciclib consistently lowered the expression of CD44 and TCF7L2 in both parental and sphere cells by inhibiting GSK3β phosphorylation. A pharmacological GSK3β inhibitor produced similar effects, reinforcing the existence of a GSK3β-CD44/TCF7L2 axis. Moreover, orthotopic xenografts confirmed reduced tumor growth and CD44 expression in vivo. Analyses of TCGA and CGGA datasets revealed that the mesenchymal GBM subtype (MES-GBM), linked with poor outcomes, exhibits elevated EMT gene expression. Treatment of MES-like LN229 cells with Abemaciclib resulted in decreased phosphorylation of GSK3β and reductions in EMT-related gene expression. Our findings highlight a novel EMT-suppressive action of Abemaciclib, illustrating its therapeutic potential for targeting the CSCs and for treating the MES-GBM. This research provides mechanistic insights and justification for repurposing Abemaciclib as targeted therapies for aggressive glioblastoma. 

摘要翻译：

多形性胶质母细胞瘤（GBM）是一种侵袭性脑肿瘤，其进展部分由癌症干细胞（CSCs）驱动。阿贝西利展现出治疗GBM的潜力，但其除RB磷酸化抑制之外的作用机制尚不完全明确。本研究揭示，阿贝西利通过GSK3β介导的CD44和TCF7L2调控影响上皮间质转化（EMT）通路，从而抑制GBM细胞球体形成。阿贝西利处理显著阻碍了GBM细胞的球体形成能力，转录组分析表明EMT通路受到抑制。从机制上，阿贝西利通过抑制GSK3β磷酸化，在亲代细胞和球体细胞中持续降低CD44和TCF7L2的表达。药理学的GSK3β抑制剂可产生类似效应，证实了GSK3β-CD44/TCF7L2轴的存在。此外，原位移植瘤实验证实该治疗可抑制体内肿瘤生长并降低CD44表达。对TCGA和CGGA数据库的分析显示，与不良预后相关的间质型GBM亚型（MES-GBM）呈现EMT基因表达上调。用阿贝西利处理MES样LN229细胞后，GSK3β磷酸化水平降低，EMT相关基因表达下降。我们的研究结果揭示了阿贝西利一种新型的EMT抑制机制，证明了其靶向癌症干细胞及治疗间质型GBM的治疗潜力。本研究为阿贝西利重新用于侵袭性胶质母细胞瘤的靶向治疗提供了机制依据和理论支持。

原文链接：

Abemaciclib impairs glioblastoma sphere formation by targeting the GSK3β-mediated transcriptional regulation of CD44 and TCF7L2