Constitutive activation of Notch2 signalling confers chemoresistance to neural stem cells via transactivation of fibroblast growth factor receptor-1

Abstract

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. Keywords: Chemoresistance, FGFR1, Glioma, Neural stem cells, Notch2