Tomé Mercedes, Tchorz Jan, Gassmann Martin, Bettler Bernhard
Department of Biomedicine, Pharmazentrum, University of Basel, 4056 Basel, Switzerland.
Department of Biomedicine, Pharmazentrum, University of Basel, 4056 Basel, Switzerland.
Stem Cell Res. 2019 Mar;35:101390. doi: 10.1016/j.scr.2019.101390. Epub 2019 Feb 7.
Notch signalling regulates neural stem cell (NSC) proliferation, differentiation and survival for the correct development and functioning of the central nervous system. Overactive Notch2 signalling has been associated with poor prognosis of aggressive brain tumours, such as glioblastoma multiforme (GBM). We recently reported that constitutive expression of the Notch2 intracellular domain (N2ICD) enhances proliferation and gliogenesis in NSCs. Here, we investigated the mechanism by which Notch2 promotes resistance to apoptosis of NSCs to cytotoxic insults. We performed ex vivo studies using NSC cultures from transgenic mice constitutively expressing N2ICD. These NSCs expressed increased levels of pro-survival factors and lack an apoptotic response to the topoisomerase inhibitor etoposide, not showing neither mitochondrial damage nor caspase activation. Interestingly, Notch2 signalling also regulated chemoresistance of human GBM cells to etoposide. We also identified a signalling crosstalk with FGF signalling pathway involved in this resistance to apoptosis of NSCs. Aberrant Notch2 expression enhances fibroblast growth factor receptor-1 (FGFR1) activity to specifically target the AKT-GSK3 signalling pathway to block apoptosis. These results have implications for understanding molecular changes involved in both tumorigenesis and therapy resistance.
Notch信号通路调节神经干细胞（NSC）的增殖、分化和存活，以确保中枢神经系统的正常发育和功能。Notch2信号通路过度激活与侵袭性脑肿瘤（如多形性胶质母细胞瘤，GBM）的不良预后相关。我们最近报道，Notch2细胞内结构域（N2ICD）的组成性表达增强了神经干细胞的增殖和胶质细胞生成。在此，我们研究了Notch2促进神经干细胞对细胞毒性损伤的抗凋亡机制。我们使用来自组成性表达N2ICD的转基因小鼠的神经干细胞培养物进行了体外研究。这些神经干细胞表达的促存活因子水平增加，并且对拓扑异构酶抑制剂依托泊苷缺乏凋亡反应，既未显示线粒体损伤也未显示半胱天冬酶激活。有趣的是，Notch2信号通路还调节了人类GBM细胞对依托泊苷的化疗耐药性。我们还确定了与参与神经干细胞这种抗凋亡反应的FGF信号通路的信号串扰。异常的Notch2表达增强成纤维细胞生长因子受体-1（FGFR1）活性，以特异性靶向AKT-GSK3信号通路来阻断凋亡。这些结果对于理解肿瘤发生和治疗耐药中涉及的分子变化具有重要意义。
