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Serine-dependent redox homeostasis regulates glioblastoma cell survival
BACKGROUND: The amino acid serine is an important substrate for biosynthesis and redox homeostasis. We investigated whether glioblastoma (GBM) cells are dependent on serine for survival under conditions of the tumour microenvironment. METHODS: Serine availability in GBM cells was modulated pharmacol...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188854/ https://www.ncbi.nlm.nih.gov/pubmed/32203214 http://dx.doi.org/10.1038/s41416-020-0794-x |
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author | Engel, Anna L. Lorenz, Nadja I. Klann, Kevin Münch, Christian Depner, Cornelia Steinbach, Joachim P. Ronellenfitsch, Michael W. Luger, Anna-Luisa |
author_facet | Engel, Anna L. Lorenz, Nadja I. Klann, Kevin Münch, Christian Depner, Cornelia Steinbach, Joachim P. Ronellenfitsch, Michael W. Luger, Anna-Luisa |
author_sort | Engel, Anna L. |
collection | PubMed |
description | BACKGROUND: The amino acid serine is an important substrate for biosynthesis and redox homeostasis. We investigated whether glioblastoma (GBM) cells are dependent on serine for survival under conditions of the tumour microenvironment. METHODS: Serine availability in GBM cells was modulated pharmacologically, genetically and by adjusting serine and glycine concentrations in the culture medium. Cells were investigated for regulation of serine metabolism, proliferation, sensitivity to hypoxia-induced cell death and redox homeostasis. RESULTS: Hypoxia-induced expression of phosphoglycerate dehydrogenase (PHGDH) and the mitochondrial serine hydroxymethyltransferase (SHMT2) was observed in three of five tested glioma cell lines. Nuclear factor erythroid 2-related factor (Nrf) 2 activation also induced PHGDH and SHMT2 expression in GBM cells. Low levels of endogenous PHGDH as well as PHGDH gene suppression resulted in serine dependency for cell growth. Pharmacological inhibition of PHGDH with CBR-5884 reduced proliferation and sensitised cells profoundly to hypoxia-induced cell death. This effect was accompanied by an increase in reactive oxygen species and a decrease in the NADPH/NADP(+) ratio. Similarly, hypoxia-induced cell death was enhanced by PHGDH gene suppression and reduced by PHGDH overexpression. CONCLUSIONS: Serine facilitates adaptation of GBM cells to conditions of the tumour microenvironment and its metabolism could be a plausible therapeutic target. |
format | Online Article Text |
id | pubmed-7188854 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-71888542021-03-17 Serine-dependent redox homeostasis regulates glioblastoma cell survival Engel, Anna L. Lorenz, Nadja I. Klann, Kevin Münch, Christian Depner, Cornelia Steinbach, Joachim P. Ronellenfitsch, Michael W. Luger, Anna-Luisa Br J Cancer Article BACKGROUND: The amino acid serine is an important substrate for biosynthesis and redox homeostasis. We investigated whether glioblastoma (GBM) cells are dependent on serine for survival under conditions of the tumour microenvironment. METHODS: Serine availability in GBM cells was modulated pharmacologically, genetically and by adjusting serine and glycine concentrations in the culture medium. Cells were investigated for regulation of serine metabolism, proliferation, sensitivity to hypoxia-induced cell death and redox homeostasis. RESULTS: Hypoxia-induced expression of phosphoglycerate dehydrogenase (PHGDH) and the mitochondrial serine hydroxymethyltransferase (SHMT2) was observed in three of five tested glioma cell lines. Nuclear factor erythroid 2-related factor (Nrf) 2 activation also induced PHGDH and SHMT2 expression in GBM cells. Low levels of endogenous PHGDH as well as PHGDH gene suppression resulted in serine dependency for cell growth. Pharmacological inhibition of PHGDH with CBR-5884 reduced proliferation and sensitised cells profoundly to hypoxia-induced cell death. This effect was accompanied by an increase in reactive oxygen species and a decrease in the NADPH/NADP(+) ratio. Similarly, hypoxia-induced cell death was enhanced by PHGDH gene suppression and reduced by PHGDH overexpression. CONCLUSIONS: Serine facilitates adaptation of GBM cells to conditions of the tumour microenvironment and its metabolism could be a plausible therapeutic target. Nature Publishing Group UK 2020-03-17 2020-04-28 /pmc/articles/PMC7188854/ /pubmed/32203214 http://dx.doi.org/10.1038/s41416-020-0794-x Text en © The Author(s) 2020, corrected publication 2021 https://creativecommons.org/licenses/by/4.0/Open Access This 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Engel, Anna L. Lorenz, Nadja I. Klann, Kevin Münch, Christian Depner, Cornelia Steinbach, Joachim P. Ronellenfitsch, Michael W. Luger, Anna-Luisa Serine-dependent redox homeostasis regulates glioblastoma cell survival |
title | Serine-dependent redox homeostasis regulates glioblastoma cell survival |
title_full | Serine-dependent redox homeostasis regulates glioblastoma cell survival |
title_fullStr | Serine-dependent redox homeostasis regulates glioblastoma cell survival |
title_full_unstemmed | Serine-dependent redox homeostasis regulates glioblastoma cell survival |
title_short | Serine-dependent redox homeostasis regulates glioblastoma cell survival |
title_sort | serine-dependent redox homeostasis regulates glioblastoma cell survival |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188854/ https://www.ncbi.nlm.nih.gov/pubmed/32203214 http://dx.doi.org/10.1038/s41416-020-0794-x |
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