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Aggressive migration in acidic pH of a glioblastoma cancer stem cell line in vitro is independent of ASIC and K(Ca)3.1 ion channels, but involves phosphoinositide 3-kinase
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 mo...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Springer Berlin Heidelberg
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9908655/ https://www.ncbi.nlm.nih.gov/pubmed/36522586 http://dx.doi.org/10.1007/s00424-022-02781-w |
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author | Cortés Franco, Klaus-Daniel Brakmann, Ilka C. Feoktistova, Maria Panayotova-Dimitrova, Diana Gründer, Stefan Tian, Yuemin |
author_facet | Cortés Franco, Klaus-Daniel Brakmann, Ilka C. Feoktistova, Maria Panayotova-Dimitrova, Diana Gründer, Stefan Tian, Yuemin |
author_sort | Cortés Franco, Klaus-Daniel |
collection | PubMed |
description | 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 Ca(2+)-activated K(+) channel KCa3.1 (KCNN4) and phosphoinositide 3-kinase (PI3K). While pharmacological blockade of K(Ca)3.1 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. |
format | Online Article Text |
id | pubmed-9908655 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Springer Berlin Heidelberg |
record_format | MEDLINE/PubMed |
spelling | pubmed-99086552023-02-10 Aggressive migration in acidic pH of a glioblastoma cancer stem cell line in vitro is independent of ASIC and K(Ca)3.1 ion channels, but involves phosphoinositide 3-kinase Cortés Franco, Klaus-Daniel Brakmann, Ilka C. Feoktistova, Maria Panayotova-Dimitrova, Diana Gründer, Stefan Tian, Yuemin Pflugers Arch Signaling and Cell Physiology 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 Ca(2+)-activated K(+) channel KCa3.1 (KCNN4) and phosphoinositide 3-kinase (PI3K). While pharmacological blockade of K(Ca)3.1 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. Springer Berlin Heidelberg 2022-12-16 2023 /pmc/articles/PMC9908655/ /pubmed/36522586 http://dx.doi.org/10.1007/s00424-022-02781-w Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Signaling and Cell Physiology Cortés Franco, Klaus-Daniel Brakmann, Ilka C. Feoktistova, Maria Panayotova-Dimitrova, Diana Gründer, Stefan Tian, Yuemin Aggressive migration in acidic pH of a glioblastoma cancer stem cell line in vitro is independent of ASIC and K(Ca)3.1 ion channels, but involves phosphoinositide 3-kinase |
title | Aggressive migration in acidic pH of a glioblastoma cancer stem cell line in vitro is independent of ASIC and K(Ca)3.1 ion channels, but involves phosphoinositide 3-kinase |
title_full | Aggressive migration in acidic pH of a glioblastoma cancer stem cell line in vitro is independent of ASIC and K(Ca)3.1 ion channels, but involves phosphoinositide 3-kinase |
title_fullStr | Aggressive migration in acidic pH of a glioblastoma cancer stem cell line in vitro is independent of ASIC and K(Ca)3.1 ion channels, but involves phosphoinositide 3-kinase |
title_full_unstemmed | Aggressive migration in acidic pH of a glioblastoma cancer stem cell line in vitro is independent of ASIC and K(Ca)3.1 ion channels, but involves phosphoinositide 3-kinase |
title_short | Aggressive migration in acidic pH of a glioblastoma cancer stem cell line in vitro is independent of ASIC and K(Ca)3.1 ion channels, but involves phosphoinositide 3-kinase |
title_sort | aggressive migration in acidic ph of a glioblastoma cancer stem cell line in vitro is independent of asic and k(ca)3.1 ion channels, but involves phosphoinositide 3-kinase |
topic | Signaling and Cell Physiology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9908655/ https://www.ncbi.nlm.nih.gov/pubmed/36522586 http://dx.doi.org/10.1007/s00424-022-02781-w |
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