ArticlePLoS genetics2010
Lactic acidosis triggers starvation response with paradoxical induction of TXNIP through MondoA.
Article in PLoS genetics, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 89 papers.
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Who cites it
89 citing papers in PubMed, 141 citations in OpenAlex.
- The influence of low-carbohydrate diets on the metabolic response to androgen-deprivation therapy in prostate cancer.The Prostate · 2021Trial
- No evident dose-response relationship between cellular ROS level and its cytotoxicity--a paradoxical issue in ROS-based cancer therapy.Scientific reports · 2014Trial
- Acidosis-associated gene signature defines novel subtypes and dual-target therapeutic candidates in breast cancer.Journal of translational medicine · 2026Article
- AMPK agonism optimizes the in vivo activation and antileukemic efficacy of chimeric antigen receptor T cells.Journal for immunotherapy of cancer · 2025Article
- Whole body MondoA deletion protects against diet-induced obesity through uncontrolled multi-organ substrate utilization and futile cycling.bioRxiv : the preprint server for biology · 2025Article
- Article
- The reciprocal effects of autophagy and the Warburg effect in pancreatic ductal adenocarcinoma: an in vitro study.Medical oncology (Northwood, London, England) · 2025Article
- Intracellular acidification and glycolysis modulate inflammatory pathway in senescent cells.Journal of biochemistry · 2024Article
- Systemic Deletion of ARRDC4 Improves Cardiac Reserve and Exercise Capacity in Diabetes.Circulation research · 2024Article
- Spatially resolved analysis of microenvironmental gradient impact on cancer cell phenotypes.Science advances · 2024Article
- Article
- Environmental Determinants of Ferroptosis in Cancer.Cancers · 2023Review
- Review
- MEK1-dependent MondoA phosphorylation regulates glucose uptake in response to ketone bodies in colorectal cancer cells.Cancer science · 2023Article
- Sepsis, pyruvate, and mitochondria energy supply chain shortage.Journal of leukocyte biology · 2022Review
- Interaction of ARRDC4 With GLUT1 Mediates Metabolic Stress in the Ischemic Heart.Circulation research · 2022Article
- 3-Bromopyruvic acid regulates glucose metabolism by targeting the c-Myc/TXNIP axis and induces mitochondria-mediated apoptosis in TNBC cells.Experimental and therapeutic medicine · 2022Article
- Thioredoxin-Interacting Protein in Cancer and Diabetes.Antioxidants & redox signaling · 2022Review
- MESH1 knockdown triggers proliferation arrest through TAZ repression.Cell death & disease · 2022Article
- Review
29 more citing papers are in PubMed but not listed here.
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Authors and funding
10 authors at 5 institutions in 2 countries.
Funding
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.