ArticleOncotarget2016
HIF-1-alpha links mitochondrial perturbation to the dynamic acquisition of breast cancer tumorigenicity.
Article in Oncotarget, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
20 citing papers in PubMed, 27 citations in OpenAlex.
- Oncometabolites in Cancer Metabolism: Mechanistic Insights and Biomarker Potential- A Narrative Review.Health science reports · 2026Article
- Exploratory Multi-Level Analysis of the HIF Axis in Clear-Cell Renal Cell Carcinoma and Evaluation of GN44028 as an Experimental HIF Pathway-Modulating Compound.International journal of molecular sciences · 2026Article
- Metformin drives HIF-1α-mediated dual metabolic reprogramming to enhance γδ T cell therapy in triple-negative breast cancer.Cancer immunology, immunotherapy : CII · 2026Article
- The Use of Patient-Derived Organoids in the Study of Molecular Metabolic Adaptation in Breast Cancer.International journal of molecular sciences · 2024Review
- Mitochondrial leak metabolism induces the Spemann-Mangold Organizer via Hif-1α in Xenopus.Developmental cell · 2023Article
- Obesity promotes radioresistance through SERPINE1-mediated aggressiveness and DNA repair of triple-negative breast cancer.Cell death & disease · 2023Article
- Regulation of Metabolic Plasticity in Cancer Stem Cells and Implications in Cancer Therapy.Cancers · 2022Review
- Hyperglycemia alters N-glycans on colon cancer cells through increased production of activated monosaccharides.Glycoconjugate journal · 2022Article
- Review
- Metabolomic Impact of Lidocaine on a Triple Negative Breast Cancer Cell Line.Frontiers in pharmacology · 2022Article
- mTOR/α-ketoglutarate-mediated signaling pathways in the context of brain neurodegeneration and neuroprotection.BBA advances · 2022Article
- Role of hypoxia inducible factor-1 in cancer stem cells (Review).Molecular medicine reports · 2021Review
- The Aging Metabolome-Biomarkers to Hub Metabolites.Proteomics · 2020Review
- The Shuganhuazheng Formula in Triple-Negative Breast Cancer: A Study Based on Network Pharmacology and In Vivo Experiments.Evidence-based complementary and alternative medicine : eCAM · 2020Article
- Hypoxia promotes proliferation of pituitary adenomas by HIF-1α/ALKBH5 signalingInternational journal of clinical and experimental pathology · 2020Article
- Review
- Mitochondrial Flexibility of Breast Cancers: A Growth Advantage and a Therapeutic Opportunity.Cells · 2019Review
- When fats commit crimes: fatty acid metabolism, cancer stemness and therapeutic resistance.Cancer communications (London, England) · 2018Review
- Methyl jasmonate leads to necrosis and apoptosis in hepatocellular carcinoma cells via inhibition of glycolysis and represses tumor growth in mice.Oncotarget · 2017Article
- The α-ketoglutarate dehydrogenase complex in cancer metabolic plasticity.Cancer & metabolism · 2017Review
Corrections and comments
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Authors and funding
11 authors at 5 institutions in 3 countries.
Funding
Abstract
Up-regulation of hypoxia-inducible factor-1α (HIF-1α), even in normoxia, is a common feature of solid malignancies. However, the mechanisms of increased HIF-1α abundance, and its role in regulating breast cancer plasticity are not fully understood. We have previously demonstrated that dimethyl-2-ketoglutarate (DKG), a widely used cell membrane-permeable α-ketoglutarate (α-KG) analogue, transiently stabilizes HIF-1α by inhibiting prolyl hydroxylase 2. Here, we report that breast cancer tumorigenicity can be acquired through prolonged treatment with DKG. Our results indicate that, in response to prolonged DKG treatment, mitochondrial respiration becomes uncoupled, leading to the accumulation of succinate and fumarate in breast cancer cells. Further, we found that an early increase in the oxygen flux rate was accompanied by a delayed enhancement of glycolysis. Together, our results indicate that these events trigger a dynamic enrichment for cells with pluripotent/stem-like cell markers and tumorsphere-forming capacity. Moreover, DKG-mediated metabolic reprogramming results in HIF-1α induction and reductive carboxylation pathway activation. Both HIF-1α accumulation and the tumor-promoting metabolic state are required for DKG-promoted tumor repopulation capacity in vivo. Our data suggest that mitochondrial adaptation to DKG elevates the ratio of succinate or fumarate to α-KG, which in turn stabilizes HIF-1α and reprograms breast cancer cells into a stem-like state. Therefore, our results demonstrate that metabolic regulation, with succinate and/or fumarate accumulation, governs the dynamic transition of breast cancer tumorigenic states and we suggest that HIF-1α is indispensable for breast cancer tumorigenicity.
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Registered trials
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.