ANO1 regulates the maintenance of stemness in glioblastoma stem cells by stabilizing EGFRvIII

Kim, Hee Jin; Kim, Jeong Yub; Jung, Chan Woong; An, Joon Yong; Kim, Eun Ho; Kim, Ki Hong; Lee, Sang Pyung; Park, Jae Yong; Park, Myung Jin

doi:10.1038/s41388-020-01612-5

Cited by 8 publications

(9 citation statements)

References 51 publications

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“…In EGFRvIII overexpressing glioma cells, angiogenesis and tumor growth were promoted by EGFRvIII-mediated activation of NF-κB ( Bonavia et al, 2012 ). EGFRvIII is also linked to self-renewal of GBM cells and connected to GBM stem-like cell populations ( Emlet et al, 2014 ; Kim et al, 2021 ). Consistently, EGFRvIII and EGFR are downregulated upon differentiation of GBM neurospheres as well as inhibited EGFR signaling induced differentiation with decreased tumorigenic and stem-like cell potential ( Stockhausen et al, 2014 ).…”

Section: Somatic Mutations Affecting Nf-κb Activation In the Context ...mentioning

confidence: 99%

NF-κB in neurodegenerative diseases: Recent evidence from human genetics

Kaltschmidt

Helweg

Greiner

et al. 2022

Front. Mol. Neurosci.

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The transcription factor NF-κB is commonly known to drive inflammation and cancer progression, but is also a crucial regulator of a broad range of cellular processes within the mammalian nervous system. In the present review, we provide an overview on the role of NF-κB in the nervous system particularly including its constitutive activity within cortical and hippocampal regions, neuroprotection as well as learning and memory. Our discussion further emphasizes the increasing role of human genetics in neurodegenerative disorders, namely, germline mutations leading to defects in NF-κB-signaling. In particular, we propose that loss of function mutations upstream of NF-κB such as ADAM17, SHARPIN, HOIL, or OTULIN affect NF-κB-activity in Alzheimer’s disease (AD) patients, in turn driving anatomical defects such as shrinkage of entorhinal cortex and the limbic system in early AD. Similarly, E3 type ubiquitin ligase PARKIN is positively involved in NF-κB signaling. PARKIN loss of function mutations are most frequently observed in Parkinson’s disease patients. In contrast to AD, relying on germline mutations of week alleles and a disease development over decades, somatic mutations affecting NF-κB activation are commonly observed in cells derived from glioblastoma multiforme (GBM), the most common malignant primary brain tumor. Here, our present review particularly sheds light on the mutual exclusion of either the deletion of NFKBIA or amplification of epidermal growth factor receptor (EGFR) in GBM, both resulting in constitutive NF-κB-activity driving tumorigenesis. We also discuss emerging roles of long non-coding RNAs such as HOTAIR in suppressing phosphorylation of IκBα in the context of GBM. In summary, the recent progress in the genetic analysis of patients, particularly those suffering from AD, harbors the potential to open up new vistas for research and therapy based on TNFα/NF-κB pathway and neuroprotection.

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Section: Somatic Mutations Affecting Nf-κb Activation In the Context ...mentioning

confidence: 99%

NF-κB in neurodegenerative diseases: Recent evidence from human genetics

Kaltschmidt

Helweg

Greiner

et al. 2022

Front. Mol. Neurosci.

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Section: Anos In Cancermentioning

confidence: 99%

“…ANO1 is expressed in glioma cancer cell lines and patient glioma tissues, and expression correlates with a high pathological grade [ 133 , 137 , 142 , 158 , 159 ]. Furthermore, several studies have shown that ANO1 knockdown reduces cell proliferation, migration, and invasion of glioma cells in vitro, suggesting a critical role in brain cancer cell function [ 137 , 142 , 159 ]. Although the precise mechanisms of ANO1 in glioma progression remain unclear, it was first suggested that ANO1 expression is associated with activation of the nuclear factor-κB (NF-κB) signalling pathway [ 137 ].…”

Section: Anos In Cancermentioning

confidence: 99%

“…Although the precise mechanisms of ANO1 in glioma progression remain unclear, it was first suggested that ANO1 expression is associated with activation of the nuclear factor-κB (NF-κB) signalling pathway [ 137 ]. More recently it has been shown that ANO1 directly interacts with and stabilises EGFRvIII in glioma cells [ 142 ]. Importantly, the oncogenic function and constitutive activity of EGFRvIII is largely dependent on its stability within the plasma membrane, as determined by its ability to continuously trans-phosphorylate itself and resist internalization and degradation [ 160 , 161 , 162 ].…”

Section: Anos In Cancermentioning

confidence: 99%

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Anoctamins and Calcium Signalling: An Obstacle to EGFR Targeted Therapy in Glioblastoma?

Dewdney

Ursich

Fletcher

et al. 2022

Cancers

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Glioblastoma is the most common form of high-grade glioma in adults and has a poor survival rate with very limited treatment options. There have been no significant advancements in glioblastoma treatment in over 30 years. Epidermal growth factor receptor is upregulated in most glioblastoma tumours and, therefore, has been a drug target in recent targeted therapy clinical trials. However, while many inhibitors and antibodies for epidermal growth factor receptor have demonstrated promising anti-tumour effects in preclinical models, they have failed to improve outcomes for glioblastoma patients in clinical trials. This is likely due to the highly plastic nature of glioblastoma tumours, which results in therapeutic resistance. Ion channels are instrumental in the development of many cancers and may regulate cellular plasticity in glioblastoma. This review will explore the potential involvement of a class of calcium-activated chloride channels called anoctamins in brain cancer. We will also discuss the integrated role of calcium channels and anoctamins in regulating calcium-mediated signalling pathways, such as epidermal growth factor signalling, to promote brain cancer cell growth and migration.

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“…22 The epidermal growth factor receptor variant III (EGFRvIII), in contrast, reportedly induces in glioblastoma cells the proneural stem cell markers Notch1, Sox2, nestin and prominin-1 (CD133) and suppresses expression of the astrocytic differentiation marker GFAP (glial fibrillary acidic protein). [24][25][26] In primary culture a mesenchymal GSC phenotype is characterized beyond its transcriptional profile (that includes upregulation of ALDH1A3) by a more cell culture-dish adherent growth morphology, and a higher radioresistance 18 as well as by faster migration and invasion 27,28 than the proneural GSC phenotype that is characterized in culture by formation of neuro(glioma)spheres.…”

Section: Introductionmentioning

confidence: 99%

Patient‐individual phenotypes of glioblastoma stem cells are conserved in culture and associate with radioresistance, brain infiltration and patient prognosis

Ganser

Eckert

Riedel

et al. 2022

Intl Journal of Cancer

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Identification of prognostic or predictive molecular markers in glioblastoma resection specimens may lead to strategies for therapy stratification and personalized treatment planning. Here, we analyzed in primary glioblastoma stem cell (pGSC) cultures the mRNA abundances of seven stem cell (MSI1, Notch1, nestin, Sox2, Oct4, FABP7 and ALDH1A3), and three radioresistance or invasion markers (CXCR4, IK Ca and BK Ca ). From these abundances, an mRNA signature was deduced which describes the mesenchymal-to-proneural expression profile of an individual GSC culture. To assess its functional significance, we associated the GSC mRNA signature with the clonogenic survival after irradiation with 4 Gy and the fibrin matrix invasion of the GSC cells. In addition, we compared the molecular pGSC mRNA signature with the tumor recurrence pattern and the overall survival of the glioblastoma patients from whom the pGSC cultures were derived. As a result, the molecular pGSC mRNA signature correlated positively with the pGSC radioresistance and matrix invasion capability in vitro. Moreover, patients with a mesenchymal (>median) mRNA signature in their pGSC cultures exhibited predominantly a multifocal tumor recurrence and a significantly (univariate log rank test) shorter overall survival than patients with proneural (≤median mRNA signature) pGSCs. The tumors of the latter recurred predominately unifocally. We conclude that our pGSC cultures induce/select those cell subpopulations of the heterogeneous brain tumor that determine disease progression and therapy outcome. In addition, we further postulate a clinically relevant

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ANO1 regulates the maintenance of stemness in glioblastoma stem cells by stabilizing EGFRvIII

Cited by 8 publications

References 51 publications

NF-κB in neurodegenerative diseases: Recent evidence from human genetics

NF-κB in neurodegenerative diseases: Recent evidence from human genetics

Anoctamins and Calcium Signalling: An Obstacle to EGFR Targeted Therapy in Glioblastoma?

Patient‐individual phenotypes of glioblastoma stem cells are conserved in culture and associate with radioresistance, brain infiltration and patient prognosis

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