Show simple item record Chen, JL Merl, D Peterson, CW Wu, J Liu, PY Yin, H Muoio, DM Ayer, DE West, M Chi, JT
dc.coverage.spatial United States 2011-06-21T17:31:21Z 2010-09-02
dc.identifier.citation PLoS Genet, 2010, 6 (9), pp. e1001093 - ?
dc.description.abstract 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.
dc.format.extent e1001093 - ?
dc.language ENG
dc.language.iso en_US en_US
dc.relation.ispartof PLoS Genet
dc.relation.isversionof 10.1371/journal.pgen.1001093
dc.subject Acidosis, Lactic
dc.subject Animals
dc.subject Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
dc.subject Carrier Proteins
dc.subject Cell Line, Tumor
dc.subject Glucose
dc.subject Humans
dc.subject Metabolic Networks and Pathways
dc.subject Mice
dc.subject Thioredoxins
dc.subject Time Factors
dc.subject Transcription, Genetic
dc.title Lactic acidosis triggers starvation response with paradoxical induction of TXNIP through MondoA.
dc.title.alternative en_US
dc.type Journal Article
dc.description.version Version of Record en_US 2010-9-0 en_US
duke.description.endpage e1001093 en_US
duke.description.issue 9 en_US
duke.description.startpage e1001093 en_US
duke.description.volume 6 en_US
dc.relation.journal Plos Genetics en_US
pubs.issue 9
pubs.organisational-group /Duke
pubs.organisational-group /Duke/School of Medicine
pubs.organisational-group /Duke/School of Medicine/Basic Science Departments
pubs.organisational-group /Duke/School of Medicine/Basic Science Departments/Molecular Genetics and Microbiology
pubs.organisational-group /Duke/School of Medicine/Basic Science Departments/Pharmacology & Cancer Biology
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments/Medicine
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments/Medicine/Medicine, Endocrinology, Metabolism, and Nutrition
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments/Medicine/Medicine, Rheumatology and Immunology
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments/Radiation Oncology
pubs.organisational-group /Duke/School of Medicine/Institutes and Centers
pubs.organisational-group /Duke/School of Medicine/Institutes and Centers/Duke Cancer Institute
pubs.organisational-group /Duke/School of Medicine/Institutes and Centers/Duke Molecular Physiology Institute
pubs.organisational-group /Duke/School of Medicine/Institutes and Centers/Duke Molecular Physiology Institute/Sarah Stedman Nutrition & Metabolism Center
pubs.organisational-group /Duke/Trinity College of Arts & Sciences
pubs.organisational-group /Duke/Trinity College of Arts & Sciences/Statistical Science
pubs.publication-status Published online
pubs.volume 6
dc.identifier.eissn 1553-7404

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