Abstract
Glioblastomas (GBMs) are the most prevalent and devastating primary intracranial malignancies and have extensive heterogeneity. Notch1 signaling is a more complex process in the development of numerous cell and tissue types, including gliomagenesis and progression, and is upregulated in glioma-initiating cells. However, the contradictory expression of Notch1 among lower grade gliomas and GBMs confounds our understanding of GBM biology and has made identifying effective therapies difficult. In this study, we validated that Notch1 and NF-κB(p65) are highly expressed in the classical and proneural subtypes of GBM using the data set from The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA). DAPT and shRNA targeting Notch1 decreased NF-κB(p65) expression, suppressed cell proliferation, and induced apoptosis of GBM cells in vitro and in vivo. Furthermore, we illustrated that the intracellular Notch could bind with NF-κB(p65) in GBM cells. These findings suggest that the cross-talk between Notch1 signaling and NF-κB(p65) could contribute to the proliferation and apoptosis of glioma, and this discovery could help drive the design of more effective therapies in Notch1-targeted clinical trials.
Highlights
Glioblastomas (GBMs) are the most prevalent and devastating primary intracranial malignancies and are characterized by extensive heterogeneity at cellular and molecular levels[1]
We examined the mRNA microarray data from The Cancer Genome Atlas (TCGA) (Figs. 1b, c) and the Chinese Glioma Genome Atlas (CGGA; Supplementary Figures S1b, d and e)
We found that Notch1-expressing cells colocalized with CD133
Summary
Glioblastomas (GBMs) are the most prevalent and devastating primary intracranial malignancies and are characterized by extensive heterogeneity at cellular and molecular levels[1]. In. GBMs, glioma stem cells (GSCs) or glioma-initiating cells (GICs) were identified more than a decade ago, which are Official journal of the Cell Death Differentiation Association. An evolutionarily conserved pathway that mediates direct cell–cell interactions, has been shown to regulate neural stem cells (NSCs) and GSCs during normal neurogenesis and pathological carcinogenesis, respectively. Our previous study focused on how Notch[1] signaling maintained the stem cell phenotype in GBMs7. Four Notch receptors (Notch1–4) and five Notch ligands including Jagged-1 and 2 and Delta-like-1, 3, and 4 have been identified in mammals[8]. Binding of a Jagged or Delta-like ligand on one cell to Notch on an adjacent cell triggers enzymatic cleavages that liberate the Notch intracellular domain (NICD). The NICD travels to the nucleus, where it interacts with the DNA-binding protein RBP-Jκ, activates transcription via a CSL
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