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Melatonin Treatment Triggers Metabolic and Intracellular pH Imbalance in Glioblastoma

Metabolic rewiring in glioblastoma (GBM) is linked to intra- and extracellular pH regulation. In this study, we sought to characterize the role of melatonin on intracellular pH modulation and metabolic consequences to identify the mechanisms of action underlying melatonin oncostatic effects on GBM t...

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Autores principales: Fernandez-Gil, Beatriz I., Otamendi-Lopez, Andrea, Bechtle, Alexandra, Vazquez-Ramos, Carla A., Qosja, Neda, Suarez-Meade, Paola, Sarabia-Estrada, Rachel, Jentoft, Mark E., Guerrero-Cázares, Hugo, Escames, Germaine, Schiapparelli, Paula, Quiñones-Hinojosa, Alfredo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9654239/
https://www.ncbi.nlm.nih.gov/pubmed/36359862
http://dx.doi.org/10.3390/cells11213467
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author Fernandez-Gil, Beatriz I.
Otamendi-Lopez, Andrea
Bechtle, Alexandra
Vazquez-Ramos, Carla A.
Qosja, Neda
Suarez-Meade, Paola
Sarabia-Estrada, Rachel
Jentoft, Mark E.
Guerrero-Cázares, Hugo
Escames, Germaine
Schiapparelli, Paula
Quiñones-Hinojosa, Alfredo
author_facet Fernandez-Gil, Beatriz I.
Otamendi-Lopez, Andrea
Bechtle, Alexandra
Vazquez-Ramos, Carla A.
Qosja, Neda
Suarez-Meade, Paola
Sarabia-Estrada, Rachel
Jentoft, Mark E.
Guerrero-Cázares, Hugo
Escames, Germaine
Schiapparelli, Paula
Quiñones-Hinojosa, Alfredo
author_sort Fernandez-Gil, Beatriz I.
collection PubMed
description Metabolic rewiring in glioblastoma (GBM) is linked to intra- and extracellular pH regulation. In this study, we sought to characterize the role of melatonin on intracellular pH modulation and metabolic consequences to identify the mechanisms of action underlying melatonin oncostatic effects on GBM tumor initiating cells. GBM tumor initiating cells were treated at different times with melatonin (1.5 and 3.0 mM). We analyzed melatonin’s functional effects on GBM proliferation, cell cycle, viability, stemness, and chemo-radiosensitivity. We then assessed the effects of melatonin on GBM metabolism by analyzing the mitochondrial and glycolytic parameters. We also measured the intracellular and extracellular pH. Finally, we tested the effects of melatonin on a mouse subcutaneous xenograft model. We found that melatonin downregulated LDHA and MCT4, decreasing lactate production and inducing a decrease in intracellular pH that was associated with an increase in ROS and ATP depletion. These changes blocked cell cycle progression and induced cellular death and we observed similar results in vivo. Melatonin’s cytotoxic effects on GBM were due, at least in part, to intracellular pH modulation, which has emerged as a newly identified mechanism, providing new insights into the oncostatic effect of melatonin on GBM.
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spelling pubmed-96542392022-11-15 Melatonin Treatment Triggers Metabolic and Intracellular pH Imbalance in Glioblastoma Fernandez-Gil, Beatriz I. Otamendi-Lopez, Andrea Bechtle, Alexandra Vazquez-Ramos, Carla A. Qosja, Neda Suarez-Meade, Paola Sarabia-Estrada, Rachel Jentoft, Mark E. Guerrero-Cázares, Hugo Escames, Germaine Schiapparelli, Paula Quiñones-Hinojosa, Alfredo Cells Article Metabolic rewiring in glioblastoma (GBM) is linked to intra- and extracellular pH regulation. In this study, we sought to characterize the role of melatonin on intracellular pH modulation and metabolic consequences to identify the mechanisms of action underlying melatonin oncostatic effects on GBM tumor initiating cells. GBM tumor initiating cells were treated at different times with melatonin (1.5 and 3.0 mM). We analyzed melatonin’s functional effects on GBM proliferation, cell cycle, viability, stemness, and chemo-radiosensitivity. We then assessed the effects of melatonin on GBM metabolism by analyzing the mitochondrial and glycolytic parameters. We also measured the intracellular and extracellular pH. Finally, we tested the effects of melatonin on a mouse subcutaneous xenograft model. We found that melatonin downregulated LDHA and MCT4, decreasing lactate production and inducing a decrease in intracellular pH that was associated with an increase in ROS and ATP depletion. These changes blocked cell cycle progression and induced cellular death and we observed similar results in vivo. Melatonin’s cytotoxic effects on GBM were due, at least in part, to intracellular pH modulation, which has emerged as a newly identified mechanism, providing new insights into the oncostatic effect of melatonin on GBM. MDPI 2022-11-02 /pmc/articles/PMC9654239/ /pubmed/36359862 http://dx.doi.org/10.3390/cells11213467 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Fernandez-Gil, Beatriz I.
Otamendi-Lopez, Andrea
Bechtle, Alexandra
Vazquez-Ramos, Carla A.
Qosja, Neda
Suarez-Meade, Paola
Sarabia-Estrada, Rachel
Jentoft, Mark E.
Guerrero-Cázares, Hugo
Escames, Germaine
Schiapparelli, Paula
Quiñones-Hinojosa, Alfredo
Melatonin Treatment Triggers Metabolic and Intracellular pH Imbalance in Glioblastoma
title Melatonin Treatment Triggers Metabolic and Intracellular pH Imbalance in Glioblastoma
title_full Melatonin Treatment Triggers Metabolic and Intracellular pH Imbalance in Glioblastoma
title_fullStr Melatonin Treatment Triggers Metabolic and Intracellular pH Imbalance in Glioblastoma
title_full_unstemmed Melatonin Treatment Triggers Metabolic and Intracellular pH Imbalance in Glioblastoma
title_short Melatonin Treatment Triggers Metabolic and Intracellular pH Imbalance in Glioblastoma
title_sort melatonin treatment triggers metabolic and intracellular ph imbalance in glioblastoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9654239/
https://www.ncbi.nlm.nih.gov/pubmed/36359862
http://dx.doi.org/10.3390/cells11213467
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