Lactate and glutamine support NADPH generation in cancer cells under glucose deprived conditions
| Autor: | Minfeng Ying, Xun Hu, Siying Zeng, Xiaobing Zhu, Limeng Cai, Duo You |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Medicine (General)
Glutamine Clinical Biochemistry MDH1 malate dehydrogenase 1 G6PD glucose-6-phosphate dehydrogenase Biochemistry Pentose Phosphate Pathway Mice ME1 Neoplasms Biology (General) α-KG α-ketoglutarate ALDH1L1 10-formyltetrahydrofolate dehydrogenase LDH lactate dehydrogenase Chemistry TME tumor microenvironment Isocitrate dehydrogenase Glucose deprivation Ac-CoA acetyl coenzyme A IDH1 Research Paper QH301-705.5 TCA tricarboxylic acid Malic enzyme PPP pentose phosphate pathway THF tetrahydrofolate TACE transarterial chemoembolization Pentose phosphate pathway IDH1 isocitrate dehydrogenase 1 R5-920 ROS reactive oxygen species MTHFD1 methylene tetrahydrofolate dehydrogenase 1 PDK1 pyruvate dehydrogenase kinase 1 NADPH Animals BPTES bis-2-(5-phenylacetamido-1 2 4-thiadiazol-2-yl)ethyl sulfide Lactic Acid MCT1 monocarboxylate transporter Organic Chemistry ME1 malic enzyme 1 PDH pyruvate dehydrogenase HIF-1 hypoxia-inducible factor 1 Cytosol Glucose Cancer cell Lactate OAA oxaloacetate Nampt Nicotinamide phosphoribosyltransferase NADP Homeostasis |
| Zdroj: | Redox Biology Redox Biology, Vol 46, Iss, Pp 102065-(2021) |
| ISSN: | 2213-2317 |
| DOI: | 10.1016/j.redox.2021.102065 |
| Popis: | Although glucose, through pentose phosphate pathway (PPP), is the main source to generate NADPH, solid tumors are often deprived of glucose, hence alternative metabolic pathways to maintain NADPH homeostasis in cancer cells are required. Here, we report that lactate and glutamine support NADPH production via isocitrate dehydrogenase 1 (IDH1) and malic enzyme 1 (ME1), respectively, under glucose-deprived conditions. Isotopic tracing demonstrates that lactate participates in the formation of isocitrate. Malate derived from glutamine in mitochondria shuttles to cytosol to produce NADPH. In cells cultured in the absence of glucose, knockout of IDH1 and ME1 decreases NADPH/NADP+ and GSH/GSSG, increases ROS level and facilitates cell necrosis. In 4T1 murine breast tumors, knockout of ME1 retards tumor growth in vivo, with combined ME1/IDH1 knockout more strongly suppressing tumor growth. Our findings reveal two alternative NADPH-producing pathways that cancer cells use to resist glucose starvation, reflecting the metabolic plasticity and flexibility of cancer cells adapting to nutrition stress. Graphical abstract Image 1 Highlights • Lactate and glutamine are the sources of NADPH in tumors under glucose deprivation. • Lactate supports NADPH generation and maintains redox balance in tumors by IDH1. • Glutamine supports NADPH generation and maintains redox balance in tumors by ME1. • Lactate-dependent NADPH generation is conditional on thermodynamics. • Combination of IDH1 and ME1 is crucial to the growth and metastasis of solid tumors. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|