Role of Notch Signaling Pathway in Glioblastoma Pathogenesis - PubMed (original) (raw)
Review
Role of Notch Signaling Pathway in Glioblastoma Pathogenesis
Riccardo Bazzoni et al. Cancers (Basel). 2019.
Abstract
Notch signaling is an evolutionarily conserved pathway that regulates important biological processes, such as cell proliferation, apoptosis, migration, self-renewal, and differentiation. In mammals, Notch signaling is composed of four receptors (Notch1⁻4) and five ligands (Dll1-3⁻4, Jagged1⁻2) that mainly contribute to the development and maintenance of the central nervous system (CNS). Neural stem cells (NSCs) are the starting point for neurogenesis and other neurological functions, representing an essential aspect for the homeostasis of the CNS. Therefore, genetic and functional alterations to NSCs can lead to the development of brain tumors, including glioblastoma multiforme (GBM). GBM remains an incurable disease, and the reason for the failure of current therapies and tumor relapse is the presence of a small subpopulation of tumor cells known as glioma stem cells (GSCs), characterized by their stem cell-like properties and aggressive phenotype. Growing evidence reveals that Notch signaling is highly active in GSCs, where it suppresses differentiation and maintains stem-like properties, contributing to GBM tumorigenesis and conventional-treatment resistance. In this review, we try to give a comprehensive view of the contribution of Notch signaling to GBM and its possible implication as a target for new therapeutic approaches.
Keywords: GSCs; Notch signaling pathway; glioblastoma multiforme; new therapeutic approaches.
Conflict of interest statement
The authors declare no conflict of interest.
Figures
Figure 1
Structure of human Notch receptors and ligands.
Figure 2
Schematic representation of the Notch signaling pathway. Once synthesized in the endoplasmic reticulum (①), the inactive single peptide precursor moves to the Golgi where it is cleaved by a furin-like convertase (S1 cleavage) (②) and translocates into the cell membrane. The binding with a Notch ligand (③) induces the second cleavage (S2) by a member of the disintegrin and metalloproteinases (ADAM) family (④), resulting in the formation of a membrane-tethered Notch truncated (NEXT) fragment, which is further processed in two sites (S3 and S4) by a presenilin-dependent γ-secretase complex (⑤), generating the Notch intracellular domain (NICD), the active form of the Notch receptor (⑥). The NICD can now enter into the nucleus, where it exerts its transcriptional activity (⑦). The ubiquitination of the NICD (⑧) leads to its proteasome degradation (⑨).
Figure 3
Functional effects of Notch-regulated miRNAs in glioblastoma. Red miRNAs are downregulated while the green ones are upregulated in Glioblastoma cells.
Figure 4
Other Notch-related tumorigenic aspects in the pathogenesis of Glioblastoma.
Figure 5
Potential mechanisms involved in Notch-mediated therapeutic resistance.
References
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