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Lactic Acidosis Triggers Starvation Response with Paradoxical Induction of TXNIP through MondoA

Although lactic acidosis is a prominent feature of solid tumors, we still have limited understanding of the mechanisms by which lactic acidosis influences metabolic phenotypes of cancer cells. We compared global transcriptional responses of breast cancer cells in response to three distinct tumor mic...

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Autores principales: Chen, Julia Ling-Yu, Merl, Daniel, Peterson, Christopher W., Wu, Jianli, Liu, Patrick Yantyng, Yin, Hanwei, Muoio, Deborah M., Ayer, Don E., West, Mike, Chi, Jen-Tsan
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2937306/
https://www.ncbi.nlm.nih.gov/pubmed/20844768
http://dx.doi.org/10.1371/journal.pgen.1001093
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author Chen, Julia Ling-Yu
Merl, Daniel
Peterson, Christopher W.
Wu, Jianli
Liu, Patrick Yantyng
Yin, Hanwei
Muoio, Deborah M.
Ayer, Don E.
West, Mike
Chi, Jen-Tsan
author_facet Chen, Julia Ling-Yu
Merl, Daniel
Peterson, Christopher W.
Wu, Jianli
Liu, Patrick Yantyng
Yin, Hanwei
Muoio, Deborah M.
Ayer, Don E.
West, Mike
Chi, Jen-Tsan
author_sort Chen, Julia Ling-Yu
collection PubMed
description Although lactic acidosis is a prominent feature of solid tumors, we still have limited understanding of the mechanisms by which lactic acidosis influences metabolic phenotypes of cancer cells. We compared global transcriptional responses of breast cancer cells in response to three distinct tumor microenvironmental stresses: lactic acidosis, glucose deprivation, and hypoxia. We found that lactic acidosis and glucose deprivation trigger highly similar transcriptional responses, each inducing features of starvation response. In contrast to their comparable effects on gene expression, lactic acidosis and glucose deprivation have opposing effects on glucose uptake. This divergence of metabolic responses in the context of highly similar transcriptional responses allows the identification of a small subset of genes that are regulated in opposite directions by these two conditions. Among these selected genes, TXNIP and its paralogue ARRDC4 are both induced under lactic acidosis and repressed with glucose deprivation. This induction of TXNIP under lactic acidosis is caused by the activation of the glucose-sensing helix-loop-helix transcriptional complex MondoA:Mlx, which is usually triggered upon glucose exposure. Therefore, the upregulation of TXNIP significantly contributes to inhibition of tumor glycolytic phenotypes under lactic acidosis. Expression levels of TXNIP and ARRDC4 in human cancers are also highly correlated with predicted lactic acidosis pathway activities and associated with favorable clinical outcomes. Lactic acidosis triggers features of starvation response while activating the glucose-sensing MondoA-TXNIP pathways and contributing to the “anti-Warburg” metabolic effects and anti-tumor properties of cancer cells. These results stem from integrative analysis of transcriptome and metabolic response data under various tumor microenvironmental stresses and open new paths to explore how these stresses influence phenotypic and metabolic adaptations in human cancers.
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spelling pubmed-29373062010-09-15 Lactic Acidosis Triggers Starvation Response with Paradoxical Induction of TXNIP through MondoA Chen, Julia Ling-Yu Merl, Daniel Peterson, Christopher W. Wu, Jianli Liu, Patrick Yantyng Yin, Hanwei Muoio, Deborah M. Ayer, Don E. West, Mike Chi, Jen-Tsan PLoS Genet Research Article Although lactic acidosis is a prominent feature of solid tumors, we still have limited understanding of the mechanisms by which lactic acidosis influences metabolic phenotypes of cancer cells. We compared global transcriptional responses of breast cancer cells in response to three distinct tumor microenvironmental stresses: lactic acidosis, glucose deprivation, and hypoxia. We found that lactic acidosis and glucose deprivation trigger highly similar transcriptional responses, each inducing features of starvation response. In contrast to their comparable effects on gene expression, lactic acidosis and glucose deprivation have opposing effects on glucose uptake. This divergence of metabolic responses in the context of highly similar transcriptional responses allows the identification of a small subset of genes that are regulated in opposite directions by these two conditions. Among these selected genes, TXNIP and its paralogue ARRDC4 are both induced under lactic acidosis and repressed with glucose deprivation. This induction of TXNIP under lactic acidosis is caused by the activation of the glucose-sensing helix-loop-helix transcriptional complex MondoA:Mlx, which is usually triggered upon glucose exposure. Therefore, the upregulation of TXNIP significantly contributes to inhibition of tumor glycolytic phenotypes under lactic acidosis. Expression levels of TXNIP and ARRDC4 in human cancers are also highly correlated with predicted lactic acidosis pathway activities and associated with favorable clinical outcomes. Lactic acidosis triggers features of starvation response while activating the glucose-sensing MondoA-TXNIP pathways and contributing to the “anti-Warburg” metabolic effects and anti-tumor properties of cancer cells. These results stem from integrative analysis of transcriptome and metabolic response data under various tumor microenvironmental stresses and open new paths to explore how these stresses influence phenotypic and metabolic adaptations in human cancers. Public Library of Science 2010-09-02 /pmc/articles/PMC2937306/ /pubmed/20844768 http://dx.doi.org/10.1371/journal.pgen.1001093 Text en Chen et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Chen, Julia Ling-Yu
Merl, Daniel
Peterson, Christopher W.
Wu, Jianli
Liu, Patrick Yantyng
Yin, Hanwei
Muoio, Deborah M.
Ayer, Don E.
West, Mike
Chi, Jen-Tsan
Lactic Acidosis Triggers Starvation Response with Paradoxical Induction of TXNIP through MondoA
title Lactic Acidosis Triggers Starvation Response with Paradoxical Induction of TXNIP through MondoA
title_full Lactic Acidosis Triggers Starvation Response with Paradoxical Induction of TXNIP through MondoA
title_fullStr Lactic Acidosis Triggers Starvation Response with Paradoxical Induction of TXNIP through MondoA
title_full_unstemmed Lactic Acidosis Triggers Starvation Response with Paradoxical Induction of TXNIP through MondoA
title_short Lactic Acidosis Triggers Starvation Response with Paradoxical Induction of TXNIP through MondoA
title_sort lactic acidosis triggers starvation response with paradoxical induction of txnip through mondoa
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2937306/
https://www.ncbi.nlm.nih.gov/pubmed/20844768
http://dx.doi.org/10.1371/journal.pgen.1001093
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