التفاصيل البيبلوغرافية
| العنوان: |
Metabolic priming by multiple enzyme systems supports glycolysis, HIF1α stabilisation, and human cancer cell survival in early hypoxia. |
| المؤلفون: |
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 |
| المصدر: |
EMBO Journal; Apr2024, Vol. 43 Issue 8, p1545-1569, 25p |
| مصطلحات موضوعية: |
CELL survival, CANCER cells, GLYCOLYSIS, HYPOXEMIA, MALATE dehydrogenase, NAD (Coenzyme), HYPOXIA-inducible factor 1, BREAST |
| مستخلص: |
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. Synopsis: Long term survival of cancer cells in hypoxia is dependent upon HIF1α activity for energy production. However, it is unclear how cells survive before HIF1α-transcribed genes are robustly expressed. This study investigated the early mechanism of human cancer cell survival upon hypoxia exposure. Shortly upon exposure to hypoxia, human breast cancer cells have increased glycolysis independent of HIF1α and without detectable changes in glycolytic enzyme expression. This glycolytic boost relies on NAD+ that is provided by reserve lactate dehydrogenase A (LDHA) capacity and malate dehydrogenase 1 (MDH1) activity fuelled by glutamate-oxoglutarate transaminase 1 (GOT1). However, NAD+ is still limiting for maximal flux through ATP-producing lower glycolysis, as indicated by efflux of glucose carbons to α-glycerophosphate (α-GP). Although MDH1 flux does not increase, combined inhibition of GOT1 and LDHA results in attenuated ATP production and cell survival. Consumption of α-ketoglutarate by GOT1 also limits prolyl hydroxylase activity and enables HIF1α stabilisation for long term hypoxic responses. In early hypoxia, NAD+ required for glycolytic ATP production is provided by lactate dehydrogenase A and GOT1-fuelled malate dehydrogenase 1 activities before HIF1α-mediated cell survival mechanisms are established. [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
Complementary Index |
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