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Acidosis induces reprogramming of cellular metabolism to mitigate oxidative stress
BACKGROUND: A variety of oncogenic and environmental factors alter tumor metabolism to serve the distinct cellular biosynthetic and bioenergetic needs present during oncogenesis. Extracellular acidosis is a common microenvironmental stress in solid tumors, but little is known about its metabolic inf...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4178214/ https://www.ncbi.nlm.nih.gov/pubmed/24359630 http://dx.doi.org/10.1186/2049-3002-1-23 |
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author | LaMonte, Gregory Tang, Xiaohu Chen, Julia Ling-Yu Wu, Jianli Ding, Chien-Kuang Cornelia Keenan, Melissa M Sangokoya, Carolyn Kung, Hsiu-Ni Ilkayeva, Olga Boros, László G Newgard, Christopher B Chi, Jen-Tsan |
author_facet | LaMonte, Gregory Tang, Xiaohu Chen, Julia Ling-Yu Wu, Jianli Ding, Chien-Kuang Cornelia Keenan, Melissa M Sangokoya, Carolyn Kung, Hsiu-Ni Ilkayeva, Olga Boros, László G Newgard, Christopher B Chi, Jen-Tsan |
author_sort | LaMonte, Gregory |
collection | PubMed |
description | BACKGROUND: A variety of oncogenic and environmental factors alter tumor metabolism to serve the distinct cellular biosynthetic and bioenergetic needs present during oncogenesis. Extracellular acidosis is a common microenvironmental stress in solid tumors, but little is known about its metabolic influence, particularly when present in the absence of hypoxia. In order to characterize the extent of tumor cell metabolic adaptations to acidosis, we employed stable isotope tracers to examine how acidosis impacts glucose, glutamine, and palmitate metabolism in breast cancer cells exposed to extracellular acidosis. RESULTS: Acidosis increased both glutaminolysis and fatty acid β-oxidation, which contribute metabolic intermediates to drive the tricarboxylic acid cycle (TCA cycle) and ATP generation. Acidosis also led to a decoupling of glutaminolysis and novel glutathione (GSH) synthesis by repressing GCLC/GCLM expression. We further found that acidosis redirects glucose away from lactate production and towards the oxidative branch of the pentose phosphate pathway (PPP). These changes all serve to increase nicotinamide adenine dinucleotide phosphate (NADPH) production and counter the increase in reactive oxygen species (ROS) present under acidosis. The reduced novel GSH synthesis under acidosis may explain the increased demand for NADPH to recycle existing pools of GSH. Interestingly, acidosis also disconnected novel ribose synthesis from the oxidative PPP, seemingly to reroute PPP metabolites to the TCA cycle. Finally, we found that acidosis activates p53, which contributes to both the enhanced PPP and increased glutaminolysis, at least in part, through the induction of G6PD and GLS2 genes. CONCLUSIONS: Acidosis alters the cellular metabolism of several major metabolites, which induces a significant degree of metabolic inflexibility. Cells exposed to acidosis largely rely upon mitochondrial metabolism for energy generation to the extent that metabolic intermediates are redirected away from several other critical metabolic processes, including ribose and glutathione synthesis. These alterations lead to both a decrease in cellular proliferation and increased sensitivity to ROS. Collectively, these data reveal a role for p53 in cellular metabolic reprogramming under acidosis, in order to permit increased bioenergetic capacity and ROS neutralization. Understanding the metabolic adaptations that cancer cells make under acidosis may present opportunities to generate anti-tumor therapeutic agents that are more tumor-specific. |
format | Online Article Text |
id | pubmed-4178214 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-41782142014-10-01 Acidosis induces reprogramming of cellular metabolism to mitigate oxidative stress LaMonte, Gregory Tang, Xiaohu Chen, Julia Ling-Yu Wu, Jianli Ding, Chien-Kuang Cornelia Keenan, Melissa M Sangokoya, Carolyn Kung, Hsiu-Ni Ilkayeva, Olga Boros, László G Newgard, Christopher B Chi, Jen-Tsan Cancer Metab Research BACKGROUND: A variety of oncogenic and environmental factors alter tumor metabolism to serve the distinct cellular biosynthetic and bioenergetic needs present during oncogenesis. Extracellular acidosis is a common microenvironmental stress in solid tumors, but little is known about its metabolic influence, particularly when present in the absence of hypoxia. In order to characterize the extent of tumor cell metabolic adaptations to acidosis, we employed stable isotope tracers to examine how acidosis impacts glucose, glutamine, and palmitate metabolism in breast cancer cells exposed to extracellular acidosis. RESULTS: Acidosis increased both glutaminolysis and fatty acid β-oxidation, which contribute metabolic intermediates to drive the tricarboxylic acid cycle (TCA cycle) and ATP generation. Acidosis also led to a decoupling of glutaminolysis and novel glutathione (GSH) synthesis by repressing GCLC/GCLM expression. We further found that acidosis redirects glucose away from lactate production and towards the oxidative branch of the pentose phosphate pathway (PPP). These changes all serve to increase nicotinamide adenine dinucleotide phosphate (NADPH) production and counter the increase in reactive oxygen species (ROS) present under acidosis. The reduced novel GSH synthesis under acidosis may explain the increased demand for NADPH to recycle existing pools of GSH. Interestingly, acidosis also disconnected novel ribose synthesis from the oxidative PPP, seemingly to reroute PPP metabolites to the TCA cycle. Finally, we found that acidosis activates p53, which contributes to both the enhanced PPP and increased glutaminolysis, at least in part, through the induction of G6PD and GLS2 genes. CONCLUSIONS: Acidosis alters the cellular metabolism of several major metabolites, which induces a significant degree of metabolic inflexibility. Cells exposed to acidosis largely rely upon mitochondrial metabolism for energy generation to the extent that metabolic intermediates are redirected away from several other critical metabolic processes, including ribose and glutathione synthesis. These alterations lead to both a decrease in cellular proliferation and increased sensitivity to ROS. Collectively, these data reveal a role for p53 in cellular metabolic reprogramming under acidosis, in order to permit increased bioenergetic capacity and ROS neutralization. Understanding the metabolic adaptations that cancer cells make under acidosis may present opportunities to generate anti-tumor therapeutic agents that are more tumor-specific. BioMed Central 2013-12-23 /pmc/articles/PMC4178214/ /pubmed/24359630 http://dx.doi.org/10.1186/2049-3002-1-23 Text en Copyright © 2013 LaMonte et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research LaMonte, Gregory Tang, Xiaohu Chen, Julia Ling-Yu Wu, Jianli Ding, Chien-Kuang Cornelia Keenan, Melissa M Sangokoya, Carolyn Kung, Hsiu-Ni Ilkayeva, Olga Boros, László G Newgard, Christopher B Chi, Jen-Tsan Acidosis induces reprogramming of cellular metabolism to mitigate oxidative stress |
title | Acidosis induces reprogramming of cellular metabolism to mitigate oxidative stress |
title_full | Acidosis induces reprogramming of cellular metabolism to mitigate oxidative stress |
title_fullStr | Acidosis induces reprogramming of cellular metabolism to mitigate oxidative stress |
title_full_unstemmed | Acidosis induces reprogramming of cellular metabolism to mitigate oxidative stress |
title_short | Acidosis induces reprogramming of cellular metabolism to mitigate oxidative stress |
title_sort | acidosis induces reprogramming of cellular metabolism to mitigate oxidative stress |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4178214/ https://www.ncbi.nlm.nih.gov/pubmed/24359630 http://dx.doi.org/10.1186/2049-3002-1-23 |
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