ArticleClinical oral investigations2017
Normoxic accumulation of HIF1α is associated with glutaminolysis.
Article in Clinical oral investigations, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 41 citations in OpenAlex.
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- Aspartate-β-hydroxylase and hypoxia marker expression in head and neck carcinomas: implications for HPV-associated tumors.Infectious agents and cancer · 2024Article
- Metabonomic analysis of tumor microenvironments: a mini-review.Frontiers in oncology · 2023Review
- Mitochondrial pyruvate supports lymphoma proliferation by fueling a glutamate pyruvate transaminase 2-dependent glutaminolysis pathway.Science advances · 2022Article
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- Electron Transfer Flavoprotein (ETF)Oxidative medicine and cellular longevity · 2022Article
- Role of glutamine and its metabolite ammonia in crosstalk of cancer-associated fibroblasts and cancer cells.Cancer cell international · 2021Review
- Urea as a By-Product of Ammonia Metabolism Can Be a Potential Serum Biomarker of Hepatocellular Carcinoma.Frontiers in cell and developmental biology · 2021Article
- Recent Metabolomics Analysis in Tumor Metabolism Reprogramming.Frontiers in molecular biosciences · 2021Review
- Current Understanding of the HIF-1-Dependent Metabolism in Oral Squamous Cell Carcinoma.International journal of molecular sciences · 2020Review
- SARS-CoV-2 and Glutamine: SARS-CoV-2 Triggered PathogenesisFrontiers in molecular biosciences · 2020Article
- Untargeted Metabolomics to Go beyond the Canonical Effect of Acetylsalicylic Acid.Journal of clinical medicine · 2019Article
- Causes and Consequences of A Glutamine Induced Normoxic HIF1 Activity for the Tumor Metabolism.International journal of molecular sciences · 2019Article
- Investigation of the Prognostic Role of Carbonic Anhydrase 9 (CAIX) of the Cellular mRNA/Protein Level or Soluble CAIX Protein in Patients with Oral Squamous Cell Carcinoma.International journal of molecular sciences · 2019Article
- Coordinative metabolism of glutamine carbon and nitrogen in proliferating cancer cells under hypoxia.Nature communications · 2019Article
- Glutaminolysis is required for transforming growth factor-β1-induced myofibroblast differentiation and activation.The Journal of biological chemistry · 2018Article
- Metabolic recycling of ammonia via glutamate dehydrogenase supports breast cancer biomass.Science (New York, N.Y.) · 2017Article
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Authors and funding
12 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
objectivesThe stabilization of the transcription factor and prognostic tumor marker hypoxia-inducible factor 1α (HIF1α) is considered to be crucial for cellular metabolic adaptations to hypoxia. However, HIF1α has also been shown to accumulate under normoxic conditions, although this phenomenon is poorly understood.
methodsWe investigated the conditions for normoxic HIF1α stabilization in different tumor cell lines (e.g., two mammary carcinoma cell lines and three oral squamous cell carcinoma cell lines) via Western blot analysis or immunohistochemical staining. The transcriptional activity of HIF1 was demonstrated by analyzing the messenger RNA (mRNA) expression of the HIF1 target carbonic anhydrase 9 (CA9) via PCR.
resultsOur data demonstrate that the combined incubation of tumor cells with glutamine and growth factors (e.g., EGF, insulin, and serum) mediates the normoxic accumulation of HIF1α in vitro. Consequently, the inhibition of glutaminolysis by a glutaminase inhibitor blocked the normoxic accumulation of HIF1α. Additionally, the normoxic HIF1α protein displayed nuclear translocation and transcriptional activity, which was confirmed by the induction of CA9 mRNA expression. Furthermore, the normoxic accumulation of HIF1α was associated with impaired proliferation of tumor cells. Finally, ammonia, the toxic waste product of glutaminolysis, induced a normoxic accumulation of HIF1α to the same extent as glutamine.
conclusionOur study suggests that HIF1α is involved in the regulation of glutamine metabolism and the cellular levels of the toxic metabolic waste product ammonia under normoxia. Hence, our results, together with data presented in the literature, support the hypothesis that HIF1α and its target genes play a crucial role in metabolic pathways, such as glutaminolysis and glycolysis, under both hypoxic and normoxic conditions. CLINICAL RELEVANCE: Therefore, the inhibition of HIF1α (and/or HIF1α target genes) could emerge as a promising therapeutic approach that would result in the accumulation of toxic metabolic waste products in tumor cells as well as the reduction of their nutrition and energy supply.
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