Inhibition of Notch signaling alters the phenotype of orthotopic tumors formed from glioblastoma multiforme neurosphere cells but does not hamper intracranial tumor growth regardless of endogene Notch pathway signature

Kristoffersen, Karina; Nedergaard, Mette Kjølhede; Villingshøj, Mette; Borup, Rehannah; Broholm, Helle; Kjær, Andreas; Poulsen, Hans Skovgaard; Stockhausen, Marie-Thérése

doi:10.4161/cbt.28876

Cited by 10 publications

(9 citation statements)

References 67 publications

(101 reference statements)

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“…In glioma stem cells (GSCs), Notch signaling is highly activated and contributes to maintaining stem cell-like properties [28]. The γ-secretase inhibitor prevents the release of the active NICD from the receptor and results in repression of proliferation and neurosphere formation, as well as promoting apoptosis in GBM cells [29,30]. Additionally, P75 NTR is upregulated in GBM and mediates the function of pro-BDNF to inhibit glioma cell growth [31].…”

Section: Discussionmentioning

confidence: 99%

Presenilin1 exerts antiproliferative effects by repressing the Wnt/β-catenin pathway in glioblastoma

Yang

et al. 2020

Cell Commun Signal

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Background: Glioblastoma and Alzheimer's disease (AD) are the most common and devastating diseases in the central nervous system. The dysfunction of Presenilin1 is the main reason for AD pathogenesis. However, the molecular function of Presenilin1 and its relative mechanism in glioblastoma remain unclear. Methods: Expression of presenilin1 in glioma was determined by IHC. CCK-8, colony formation, Flow cytometry, Edu staining were utilized to evaluate functions of presenilin1 on glioblastoma proliferation. The mechanism of above process was assessed by Western blotting and cell immunofluorescence. Mouse transplanting glioblastoma model and micro-MRI detection were used to verified presenilin1 function in vivo. Results: In this study, we found that all grades of glioma maintained relatively low Presenilin1 expression and that the expression of Presenilin1 in high-grade glioma was significantly lower than that in low-grade glioma. Moreover, the Presenilin1 level had a positive correlation with glioma and glioblastoma patient prognosis. Next, we determined that Presenilin1 inhibited the growth and proliferation of glioblastoma cells by downregulating CDK6, C-myc and Cyclin D1 to arrest the cell cycle at the G1/S phase. Mechanistically, Presenilin1 promoted the direct phosphorylation of β-catenin at the 45 site and indirect phosphorylation at the 33/37/41 site, then decreased the stabilized part of β-catenin and hindered its translocation from the cytoplasm to the nucleus. Furthermore, we found that Presenilin1 downregulation clearly accelerated the growth of subcutaneous glioblastoma, and Presenilin1 overexpression significantly repressed the subcutaneous and intracranial transplantation of glioblastoma by hindering β-catenin-dependent cell proliferation. Conclusion: Our data implicate the antiproliferative effect of Presenilin1 in glioblastoma by suppressing Wnt/βcatenin signaling, which may provide a novel therapeutic agent for glioblastoma.

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Section: Discussionmentioning

confidence: 99%

Presenilin1 exerts antiproliferative effects by repressing the Wnt/β-catenin pathway in glioblastoma

Yang

et al. 2020

Cell Commun Signal

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“…In particular, TRPM7 levels correlate with those of Notch1, Jagged1, Hey2, and survivin [124]. Neurosphere cultures with high Notch1 levels show a more infiltrative phenotype when compared to Notch1 low cultures [126]; furthermore, the suppression of cell migration, tumor invasion, and angiogenesis can be achieved by targeting the urokinase-type plasminogen activator/urokinase-type plasminogen activator receptor (uPA/uPAR) system in order to inhibit Notch-signaling-induced AKT, NF-κB, and ERK pathways [127]. The oncogenic role of Notch1 can also be due to the infection of human cytomegalovirus, which upregulates Notch1, ATF5 (an anti-apoptotic protein already highly expressed in Glioblastoma), and stem cell markers CD133, nestin, SOX2, OCT4, KLF4, and BMI-1 [128].…”

Section: Notch Signaling and Glioblastomamentioning

confidence: 99%

“…The suppression of cell proliferation and induction of apoptosis is mediated by the decrease of NF-κB (p65) expression through Notch inhibition [105]. Glioblastoma neurospheres with high Notch activity are more sensitive to DAPT and DAPT-treated cultures and show a more differentiated state and low Hes5 levels [126,146,147]. The combined treatment of DAPT with Iressa, an EGFR inhibitor, reduces VEGF expression and secretion when compared to single treatments.…”

Section: Notch Signaling and Glioblastomamentioning

confidence: 99%

Role of Notch Signaling Pathway in Glioblastoma Pathogenesis

Tanasi

Bentivegna

2019

Cancers

134

108

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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.

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“…In brain cancer cell lines, it was established that the suppression of Notch signaling with DAPT inhibited hypoxia-induced GSC expansion [ 41 ]; abolished the effects of STC1 on N1-ICD production, SOX2 expression, and the sphere-forming capacity [ 42 ]; reduced the CSC of CD133 + and inhibited the proliferation of SHG-44 cells [ 43 ]; suppressed the transition from CD1331/CD1442 to double-positive (DP) [ 44 ]; inhibited cell growth and reduced the sphere formation capacity in glioblastoma neurosphere cultures [ 45 ]; and downregulated HIF-1α and hes1, reduced the number of nestin + cells, increased the number of β-III-tubulin + cells, and enhanced MKI67 and neuronal differentiation [ 46 ]. However, one study showed that DAPT treatment reduced brain CSCs, but had no survival benefit for mice injected with DAPT-treated GBM neurosphere cells [ 47 ].…”

Section: Anticancer Activities Of Gsis Against Cscsmentioning

confidence: 99%

Unlocking the Secrets of Cancer Stem Cells with γ-Secretase Inhibitors: A Novel Anticancer Strategy

Ghanbari-Movahed

Momtaz

et al. 2021

Molecules

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The dysregulation of Notch signaling is associated with a wide variety of different human cancers. Notch signaling activation mostly relies on the activity of the γ-secretase enzyme that cleaves the Notch receptors and releases the active intracellular domain. It is well-documented that γ-secretase inhibitors (GSIs) block the Notch activity, mainly by inhibiting the oncogenic activity of this pathway. To date, several GSIs have been introduced clinically for the treatment of various diseases, such as Alzheimer’s disease and various cancers, and their impacts on Notch inhibition have been found to be promising. Therefore, GSIs are of great interest for cancer therapy. The objective of this review is to provide a systematic review of in vitro and in vivo studies for investigating the effect of GSIs on various cancer stem cells (CSCs), mainly by modulation of the Notch signaling pathway. Various scholarly electronic databases were searched and relevant studies published in the English language were collected up to February 2020. Herein, we conclude that GSIs can be potential candidates for CSC-targeting therapy. The outcome of our study also indicates that GSIs in combination with anticancer drugs have a greater inhibitory effect on CSCs.

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Inhibition of Notch signaling alters the phenotype of orthotopic tumors formed from glioblastoma multiforme neurosphere cells but does not hamper intracranial tumor growth regardless of endogene Notch pathway signature

Cited by 10 publications

References 67 publications

Presenilin1 exerts antiproliferative effects by repressing the Wnt/β-catenin pathway in glioblastoma

Presenilin1 exerts antiproliferative effects by repressing the Wnt/β-catenin pathway in glioblastoma

Role of Notch Signaling Pathway in Glioblastoma Pathogenesis

Unlocking the Secrets of Cancer Stem Cells with γ-Secretase Inhibitors: A Novel Anticancer Strategy

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