Serine-dependent redox homeostasis regulates glioblastoma cell survival

Abstract

Abstract 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 ofphosphoglycerate dehydrogenase (PHGDH)and the mitochondrialserine hydroxymethyltransferase (SHMT2)was observed in three of five tested glioma cell lines. Nuclear factor erythroid 2-related factor (Nrf) 2 activation also inducedPHGDHandSHMT2expression in GBM cells. Low levels of endogenous PHGDH as well asPHGDHgene 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 byPHGDHgene suppression and reduced byPHGDHoverexpression. Conclusions Serine facilitates adaptation of GBM cells to conditions of the tumour microenvironment and its metabolism could be a plausible therapeutic target.