Serine-dependent redox homeostasis regulates glioblastoma cell survival

Br J Cancer. 2020 Apr;122(9):1391-1398. doi: 10.1038/s41416-020-0794-x. Epub 2020 Mar 17.


Background: The amino acid serine is an important substrate for biosynthesis and redox homeostasis. We investigated whether glioblastoma (GBM) cells are dependent on serine for survival under conditions of the tumour microenvironment.

Methods: Serine availability in GBM cells was modulated pharmacologically, genetically and by adjusting serine and glycine concentrations in the culture medium. Cells were investigated for regulation of serine metabolism, proliferation, sensitivity to hypoxia-induced cell death and redox homeostasis.

Results: Hypoxia-induced expression of phosphoglycerate dehydrogenase (PHGDH) and the mitochondrial serine hydroxymethyltransferase (SHMT2) was observed in three of five tested glioma cell lines. Nuclear factor erythroid 2-related factor (Nrf) 2 activation also induced PHGDH and SHMT2 expression in GBM cells. Low levels of endogenous PHGDH as well as PHGDH gene suppression resulted in serine dependency for cell growth. Pharmacological inhibition of PHGDH with CBR-5884 reduced proliferation and sensitised cells profoundly to hypoxia-induced cell death. This effect was accompanied by an increase in reactive oxygen species and a decrease in the NADPH/NADP+ ratio. Similarly, hypoxia-induced cell death was enhanced by PHGDH gene suppression and reduced by PHGDH overexpression.

Conclusions: Serine facilitates adaptation of GBM cells to conditions of the tumour microenvironment and its metabolism could be a plausible therapeutic target.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Gene Expression Regulation, Neoplastic / drug effects
  • Glioblastoma / genetics
  • Glioblastoma / metabolism*
  • Glioblastoma / pathology
  • Glycine Hydroxymethyltransferase / genetics*
  • Homeostasis / drug effects
  • Humans
  • NF-E2-Related Factor 2 / genetics*
  • Oxidation-Reduction / drug effects
  • Phosphoglycerate Dehydrogenase / antagonists & inhibitors
  • Phosphoglycerate Dehydrogenase / genetics*
  • Reactive Oxygen Species / metabolism
  • Serine / metabolism
  • Tumor Microenvironment / drug effects


  • Antineoplastic Agents
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • Reactive Oxygen Species
  • Serine
  • Phosphoglycerate Dehydrogenase
  • Glycine Hydroxymethyltransferase
  • SHMT protein, human