Acidosis induces RIPK1-dependent death of glioblastoma stem cells via acid-sensing ion channel 1a

Clusmann, Jan; Franco, Klaus-Daniel Cortés; Suárez, D; Katona, István; Minguez, Maria Girbes; Boersch, Nina; Pissas, Karolos-Philippos; Vanek, Jakob; Tian, Yuemin; Gründer, Stefan

doi:10.1038/s41419-022-05139-3

Cited by 11 publications

(25 citation statements)

References 64 publications

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“…5c). These ndings are similar to the effect of acidic pH on GSCs [24]. In contrast, maintenance of mouse neurons in acidic medium for 24 hours induces ASIC-mediated cell death [25,[46][47][48][49].…”

Section: Extracellular Acidi Cation Reduces Cell Viability But Does N...supporting

confidence: 61%

“…Functional homomeric ASIC1a is also expressed in glioblastoma stem cell lines (GSCs) [22]. While ASICs do not contribute to the aggressive migration of GSCs in vitro [23], activation of ASIC1a reduces tumor sphere formation of GSCs by inducing a Nec1-dependent cell death that is related to but not identical with necroptosis [24]. Nec-1 is an inhibitor of receptor interacting protein kinase 1 (RIPK1) and it had previously been demonstrated that ASIC1a activation induces a RIPK1-dependent cell death mechanism in neurons, which could contribute to the neurodegeneration accompanying ischemic stroke [25].…”

Section: Introductionmentioning

confidence: 99%

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Functional characterization of acid-sensing ion channels in the cerebellum-originating medulloblastoma cell line DAOY and in cerebellar granule neurons

Pissas

Schilling

Tian

et al. 2023

Preprint

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Acid-sensing ion channels (ASICs) are Na+ channels that are almost ubiquitously expressed in neurons of the brain. Functional ASIC1a is also expressed in glioblastoma stem cells, where it might sense the acidic tumor microenvironment. Prolonged acidosis induces cell death in neurons and reduces tumor sphere formation in glioblastoma via activation of ASIC1a. It is currently unknown whether ASICs are expressed and involved in acid-induced cell death in other types of brain tumors. In this study, we investigated ASICs in medulloblastoma, using two established cell lines, DAOY and UW228, as in vitro models. In addition, for the first time we characterized ASICs in the most numerous neuron of the brain, the cerebellar granule cell, which shares the progenitor cell with some forms of medulloblastoma. We report compelling evidence using RT-qPCR, western blot and whole-cell patch clamp that DAOY and cerebellar granule cells, but not UW228 cells, functionally express homomeric ASIC1a. Additionally, Ca2+-imaging revealed that extracellular acidification elevated intracellular Ca2+-levels in DAOY cells independently of ASICs. Finally, we show that overexpression of RIPK3, a key component of the necroptosis pathway, renders DAOY cells susceptible to acid-induced cell death via activation of ASIC1a. Our data supports the idea that ASIC1a is an important acid sensor in brain tumors and that its activation has potential to induce cell death in tumor cells.

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Section: Extracellular Acidi Cation Reduces Cell Viability But Does N...supporting

confidence: 61%

Section: Introductionmentioning

confidence: 99%

Functional characterization of acid-sensing ion channels in the cerebellum-originating medulloblastoma cell line DAOY and in cerebellar granule neurons

Pissas

Schilling

Tian

et al. 2023

Preprint

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“…Sizes of spheres grown at pH 6.6 were smaller than those of spheres grown at pH 7.4 (Fig. 5b-c), which was expected, as the doubling time in pH 6.6 is longer for R54 GSCs [5]. It is unlikely, however, that the smaller sphere sizes affected the interpretation of this experiment, because, if anything, fewer cells should grow out of smaller spheres.…”

Section: Pi3k But Not K Ca 31 Modulates Ph-dependent Migrationmentioning

confidence: 51%

“…3d). Finally, we assessed the outgrowth of spheres using two independent R54 lines with an ASIC1a knockout [5]. Also ASIC1a knockout did not affect migration (Fig.…”

Section: Asic1 Asic2 and Asic3 Do Not Modulate Ph-dependent Migrationmentioning

confidence: 99%

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Aggressive migration in acidic pH of a glioblastoma cancer stem cell line in vitro is independent of ASIC and KCa3.1 ion channels, but involves phosphoinositide 3-kinase

Franco

Brakmann

Feoktistova

et al. 2022

Pflugers Arch - Eur J Physiol

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The microenvironment of proliferative and aggressive tumours, such as the brain tumour glioblastoma multiforme (GBM), is often acidic, hypoxic, and nutrient deficient. Acid-sensing ion channels (ASICs) are proton-sensitive Na+ channels that have been proposed to play a role in pH sensing and in modulation of cancer cell migration. We previously reported that primary glioblastoma stem cells (GSCs), which grow as multicellular tumour spheroids, express functional ASIC1a and ASIC3, whereas ASIC2a is downregulated in GSCs. Using a 2.5D migration assay, here we report that acidic pH dramatically increased migration of GSCs of the pro-neural subtype. Pharmacological blockade as well as CRISPR-Cas9-mediated gene knock-out of ASIC1a or stable overexpression of ASIC2a, however, revealed that neither ASIC1a nor ASIC3, nor downregulation of ASIC2a, mediated the aggressive migration at acidic pH. Therefore, we tested the role of two other proteins previously implicated in cancer cell migration: the Ca2+-activated K+ channel KCa3.1 (KCNN4) and phosphoinositide 3-kinase (PI3K). While pharmacological blockade of KCa3.1 did also not affect migration, blockade of PI3K decreased migration at acidic pH to control levels. In summary, our study reveals a strongly enhanced migration of GSCs at acidic pH in vitro and identifies PI3K as an important mediator of this effect.

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Targeting Acid-Sensing Ion Channels in Disease

Senescall,

Budusan,

Knezic

et al. 2024

Ion Channels as Targets in Drug Discovery

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Acidosis induces RIPK1-dependent death of glioblastoma stem cells via acid-sensing ion channel 1a

Cited by 11 publications

References 64 publications

Functional characterization of acid-sensing ion channels in the cerebellum-originating medulloblastoma cell line DAOY and in cerebellar granule neurons

Functional characterization of acid-sensing ion channels in the cerebellum-originating medulloblastoma cell line DAOY and in cerebellar granule neurons

Aggressive migration in acidic pH of a glioblastoma cancer stem cell line in vitro is independent of ASIC and KCa3.1 ion channels, but involves phosphoinositide 3-kinase

Targeting Acid-Sensing Ion Channels in Disease

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