ArticleOncogene2013
Mitochondrial activation by inhibition of PDKII suppresses HIF1a signaling and angiogenesis in cancer.
Article in Oncogene, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 106 papers.
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Who cites it
106 citing papers in PubMed, 180 citations in OpenAlex.
- Dichloroacetate should be considered with platinum-based chemotherapy in hypoxic tumors rather than as a single agent in advanced non-small cell lung cancer.Journal of cancer research and clinical oncology · 2014Trial
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- Cell-Type-Dependent Metabolic Compensation Preserves Photoreceptor Survival Through Pyruvate Kinase Isoform Balance.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Article
- Metabolic reprogramming in ischemic stroke: when glycolytic overdrive meets lipid storm.Cell death & disease · 2025Review
- Dichloroacetate and Salinomycin as Therapeutic Agents in Cancer.Medical sciences (Basel, Switzerland) · 2025Review
- Recent Advances on the Role of B Vitamins in Cancer Prevention and Progression.International journal of molecular sciences · 2025Review
- Leveraging adenosine triphosphate for cancer theranostics.Theranostics · 2025Review
- Identification of telomere-related gene subtypes and prognostic signatures in osteosarcoma.Frontiers in pharmacology · 2025Article
- Dichloroacetate for Cancer Treatment: Some Facts and Many Doubts.Pharmaceuticals (Basel, Switzerland) · 2024Review
- Modulation of hypoxia-inducible factor-1 signaling pathways in cancer angiogenesis, invasion, and metastasis by natural compounds: a comprehensive and critical review.Cancer metastasis reviews · 2024Review
- Dichloroacetic acid and rapamycin synergistically inhibit tumor progression.Journal of Zhejiang University. Science. B · 2023Article
- The expression pattern of pyruvate dehydrogenase kinases predicts prognosis and correlates with immune exhaustion in clear cell renal cell carcinoma.Scientific reports · 2023Article
- PI3K signalling at the intersection of cardio-oncology networks: cardiac safety in the era of AI.Cellular and molecular life sciences : CMLS · 2022Review
- Studying molecular signaling in major angiogenic diseases.Molecular and cellular biochemistry · 2022Review
- Targeting RNA NMolecular cancer · 2022Review
- Extracellular vesicles derived from Lactobacillus plantarum restore chemosensitivity through the PDK2-mediated glucose metabolic pathway in 5-FU-resistant colorectal cancer cells.Journal of microbiology (Seoul, Korea) · 2022Article
- Article
- Signal Transduction during Metabolic and Inflammatory Reprogramming in Pulmonary Vascular Remodeling.International journal of molecular sciences · 2022Review
- Reversing tozasertib resistance in glioma through inhibition of pyruvate dehydrogenase kinases.Molecular oncology · 2022Article
- Impact of Sodium Dichloroacetate Alone and in Combination Therapies on Lung Tumor Growth and Metastasis.International journal of molecular sciences · 2021Article
46 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
Abstract
Most solid tumors are characterized by a metabolic shift from glucose oxidation to glycolysis, in part due to actively suppressed mitochondrial function, a state that favors resistance to apoptosis. Suppressed mitochondrial function may also contribute to the activation of hypoxia-inducible factor 1α (HIF1α) and angiogenesis. We have previously shown that the inhibitor of pyruvate dehydrogenase kinase (PDK) dichloroacetate (DCA) activates glucose oxidation and induces apoptosis in cancer cells in vitro and in vivo. We hypothesized that DCA will also reverse the 'pseudohypoxic' mitochondrial signals that lead to HIF1α activation in cancer, even in the absence of hypoxia and inhibit cancer angiogenesis. We show that inhibition of PDKII inhibits HIF1α in cancer cells using several techniques, including HIF1α luciferase reporter assays. Using pharmacologic and molecular approaches that suppress the prolyl-hydroxylase (PHD)-mediated inhibition of HIF1α, we show that DCA inhibits HIF1α by both a PHD-dependent mechanism (that involves a DCA-induced increase in the production of mitochondria-derived α-ketoglutarate) and a PHD-independent mechanism, involving activation of p53 via mitochondrial-derived H(2)O(2), as well as activation of GSK3β. Effective inhibition of HIF1α is shown by a decrease in the expression of several HIF1α regulated gene products as well as inhibition of angiogenesis in vitro in matrigel assays. More importantly, in rat xenotransplant models of non-small cell lung cancer and breast cancer, we show effective inhibition of angiogenesis and tumor perfusion in vivo, assessed by contrast-enhanced ultrasonography, nuclear imaging techniques and histology. This work suggests that mitochondria-targeting metabolic modulators that increase pyruvate dehydrogenase activity, in addition to the recently described pro-apoptotic and anti-proliferative effects, suppress angiogenesis as well, normalizing the pseudo-hypoxic signals that lead to normoxic HIF1α activation in solid tumors.
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What OpenQuestion holds
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.