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Metabolic priming by multiple enzyme systems supports glycolysis, HIF1α stabilisation, and human cancer cell survival in early hypoxia.
Grimm, Fiona; Asuaje, Agustín; Jain, Aakriti; Silva Dos Santos, Mariana; Kleinjung, Jens; Nunes, Patrícia M; Gehrig, Stefanie; Fets, Louise; Darici, Salihanur; MacRae, James I; Anastasiou, Dimitrios.
Afiliação
  • Grimm F; Cancer Metabolism Laboratory, The Francis Crick Institute, 1 Midland Road, NW1 1AT, London, UK.
  • Asuaje A; Cancer Metabolism Laboratory, The Francis Crick Institute, 1 Midland Road, NW1 1AT, London, UK.
  • Jain A; Cancer Metabolism Laboratory, The Francis Crick Institute, 1 Midland Road, NW1 1AT, London, UK.
  • Silva Dos Santos M; Metabolomics Science Technology Platform, The Francis Crick Institute, 1 Midland Road, NW1 1AT, London, UK.
  • Kleinjung J; Computational Biology Science Technology Platform, The Francis Crick Institute, 1 Midland Road, NW1 1AT, London, UK.
  • Nunes PM; Cancer Metabolism Laboratory, The Francis Crick Institute, 1 Midland Road, NW1 1AT, London, UK.
  • Gehrig S; Cancer Metabolism Laboratory, The Francis Crick Institute, 1 Midland Road, NW1 1AT, London, UK.
  • Fets L; Cancer Metabolism Laboratory, The Francis Crick Institute, 1 Midland Road, NW1 1AT, London, UK.
  • Darici S; Cancer Metabolism Laboratory, The Francis Crick Institute, 1 Midland Road, NW1 1AT, London, UK.
  • MacRae JI; Metabolomics Science Technology Platform, The Francis Crick Institute, 1 Midland Road, NW1 1AT, London, UK.
  • Anastasiou D; Cancer Metabolism Laboratory, The Francis Crick Institute, 1 Midland Road, NW1 1AT, London, UK. dimitrios.anastasiou@crick.ac.uk.
EMBO J ; 43(8): 1545-1569, 2024 Apr.
Article em En | MEDLINE | ID: mdl-38485816
ABSTRACT
Adaptation to chronic hypoxia occurs through changes in protein expression, which are controlled by hypoxia-inducible factor 1α (HIF1α) and are necessary for cancer cell survival. However, the mechanisms that enable cancer cells to adapt in early hypoxia, before the HIF1α-mediated transcription programme is fully established, remain poorly understood. Here we show in human breast cancer cells, that within 3 h of hypoxia exposure, glycolytic flux increases in a HIF1α-independent manner but is limited by NAD+ availability. Glycolytic ATP maintenance and cell survival in early hypoxia rely on reserve lactate dehydrogenase A capacity as well as the activity of glutamate-oxoglutarate transaminase 1 (GOT1), an enzyme that fuels malate dehydrogenase 1 (MDH1)-derived NAD+. In addition, GOT1 maintains low α-ketoglutarate levels, thereby limiting prolyl hydroxylase activity to promote HIF1α stabilisation in early hypoxia and enable robust HIF1α target gene expression in later hypoxia. Our findings reveal that, in normoxia, multiple enzyme systems maintain cells in a primed state ready to support increased glycolysis and HIF1α stabilisation upon oxygen limitation, until other adaptive processes that require more time are fully established.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Hipóxia Celular / Subunidade alfa do Fator 1 Induzível por Hipóxia / Neoplasias Limite: Humans Idioma: En Revista: EMBO J Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Reino Unido

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Hipóxia Celular / Subunidade alfa do Fator 1 Induzível por Hipóxia / Neoplasias Limite: Humans Idioma: En Revista: EMBO J Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Reino Unido