Abstract
Fast-growing tumors satisfy their bioenergetic needs by supplementing glucose with alternative carbon sources. Cancer stem cells are the most versatile and robust cells within malignant tumors. They avoid potentially lethal metabolic and other types of stress through flexible reprogramming of relevant pathways, but it has remained unclear whether alternative carbon sources are important for the maintenance of their tumor-propagating ability. Here we assessed the ability of glycolytic and oxidative murine glioma stem cells (GSCs) to grow in an ultralow glucose medium. Sphere formation assays revealed that exogenous lactate and acetate reversed the growth impairment of oxidative GSCs in such medium. Extracellular flux analysis showed that lactate supported oxygen consumption in these cells, whereas metabolomics analysis revealed that it increased the intracellular levels of tricarboxylic acid cycle intermediates, ATP, and GTP as well as increased adenylate and guanylate charge. Lactate also reversed the depletion of choline apparent in the glucose-deprived cells as well as reprogrammed phospholipid and fatty acid biosynthesis. This metabolic reprogramming was associated with a more aggressive phenotype of intracranial tumors formed by lactate-treated GSCs. Our results thus suggest that lactate is an important alternative energetic and biosynthetic substrate for oxidative GSCs, and that it sustains their growth under conditions of glucose deprivation.
Highlights
Cancer cells require large amounts of glucose to fuel their growth
We found that the addition of 4 mM acetate had a significant rescue effect on the growth of oxidative glioma stem cells (GSCs) spheres, but this effect was not as prominent as that of equimolar lactate (Figure 1E)
In cancer cells with stemlike properties, which are able to adapt to and survive under adverse conditions, such supplementation might result in metabolic reprogramming and the emergence of stress-resistant phenotypes
Summary
Cancer cells require large amounts of glucose to fuel their growth. Glucose availability affects the acetyl coenzyme A (CoA) pool, ATP formation, redox balance, and de novo synthesis of membrane components such as phospholipids. Cancer stem cells (CSCs) are the most versatile and robust cells within malignant tumors They avoid potentially lethal conditions such as metabolic stress by reprogramming relevant pathways. Metabolic flexibility of CSCs has been linked to oncogene expression, specific transcription factors, and reprogramming in response to hypoxia [12,13,14]. It has remained unclear whether the closing of energy gaps through the adoption of alternative carbon sources is important for the growth of CSCs and CSC-based tumors
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