Lactic acidosis triggers starvation response with paradoxical induction of TXNIP through MondoA.
| dc.contributor.author | Chen, JL | |
| dc.contributor.author | Merl, D | |
| dc.contributor.author | West, M | |
| dc.contributor.author | Chi, JTA | |
| dc.contributor.editor | Gibson, Greg | |
| dc.coverage.spatial | United States | |
| dc.date.accessioned | 2011-06-21T17:31:21Z | |
| dc.date.issued | 2010-09-02 | |
| 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.description.version | Version of Record | |
| dc.identifier | ||
| dc.identifier.eissn | 1553-7404 | |
| dc.identifier.uri | ||
| dc.language | eng | |
| dc.language.iso | en_US | |
| dc.publisher | Public Library of Science (PLoS) | |
| dc.relation.ispartof | PLoS Genet | |
| dc.relation.isversionof | 10.1371/journal.pgen.1001093 | |
| dc.relation.journal | Plos Genetics | |
| 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 | ||
| dc.type | Journal article | |
| duke.contributor.orcid | West, M|0000-0002-7297-7801 | |
| duke.date.pubdate | 2010-9-0 | |
| duke.description.issue | 9 | |
| duke.description.volume | 6 | |
| pubs.author-url | ||
| pubs.begin-page | e1001093 | |
| pubs.issue | 9 | |
| pubs.organisational-group | Basic Science Departments | |
| pubs.organisational-group | Clinical Science Departments | |
| pubs.organisational-group | Duke | |
| pubs.organisational-group | Duke Cancer Institute | |
| pubs.organisational-group | Duke Molecular Physiology Institute | |
| pubs.organisational-group | Institutes and Centers | |
| pubs.organisational-group | Medicine | |
| pubs.organisational-group | Medicine, Endocrinology, Metabolism, and Nutrition | |
| pubs.organisational-group | Medicine, Rheumatology and Immunology | |
| pubs.organisational-group | Molecular Genetics and Microbiology | |
| pubs.organisational-group | Pharmacology & Cancer Biology | |
| pubs.organisational-group | Radiation Oncology | |
| pubs.organisational-group | Sarah Stedman Nutrition & Metabolism Center | |
| pubs.organisational-group | School of Medicine | |
| pubs.organisational-group | Statistical Science | |
| pubs.organisational-group | Trinity College of Arts & Sciences | |
| pubs.publication-status | Published online | |
| pubs.volume | 6 |