Lactate reprograms energy and lipid metabolism in glucose-deprived oxidative glioma stem cells

Noriaki Minami, Kazuhiro Tanaka, Takashi Sasayama, Eiji Kohmura, Hideyuki Saya, Oltea Sampetrean

Research output: Contribution to journalArticlepeer-review

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 impair-ment 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.

Original languageEnglish
Article number325
JournalMetabolites
Volume11
Issue number5
DOIs
Publication statusPublished - 2021 May

Keywords

  • Cancer stem cell
  • Glioma
  • Glioma stem cell
  • Glucose deprivation
  • Lactate
  • Lipid metabolism
  • Metabolic cooperation
  • Metabolic reprogramming
  • Metabolic symbiosis
  • Metabolism

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Biology

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