Serine-dependent redox homeostasis regulates glioblastoma cell survival

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 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.

Linking Serine/Glycine Metabolism to Radiotherapy Resistance

“…Recently, the upregulation of PHGDH and SHMT2 expression under hypoxic conditions has also been observed in certain GBM cell lines. This study has shown that high levels of PHGDH protect GBM cells from hypoxia-induced cell death and starvation conditions, sustaining redox homeostasis and maintaining NADPH/NADP+ ratio [ 116 ]. Likewise, serine/glycine metabolism was previously associated with the survival of glioma tumor cells within the hypoxic areas.…”

“…For instance, serine starvation resulted in reduced viability and impaired proliferation in p53-deficient tumors [ 153 ]. Inhibition of de novo serine/glycine biosynthesis is likely most effective in tumors that are reliant on de novo serine/glycine biosynthesis, such as PHGDH-amplified melanoma and breast cancers, as well as tumors with increased dependency on this pathway under metabolic/stress conditions, e.g., KRAS-mutated pancreatic tumors, which become insensitive to serine/glycine deprivation [ 16 , 26 ], or GBM and cMYC-amplified neuroblastomas with upregulation of this pathway in response to hypoxia [ 115 , 116 ]. However, it is important to consider the metabolic plasticity and the compensatory mechanisms following these therapeutic strategies.…”

Genetic Profiles Affect the Biological Effects of Serine on Gastric Cancer Cells

“…For instance, Engel and colleagues reported that tumor microenvironment with high serine concentration contributed to rapid cell growth in glioblastoma. Interfering serine metabolism could be a plausible therapeutic target (Engel et al, 2020). It was reported that the proliferative ability of cancer cells could be enhanced by high content of microenvironmental serine (Labuschagne et al, 2014).…”

“…For example, Saito et al reported that elevated leucine in microenvironment can promote cell proliferation in breast cancer, and induce resistance to tamoxifen (Saito et al, 2019). Engel et al found that serine content of microenvironment determined the growth and survival of glioblastoma (Engel et al, 2020). In lung cancer, the imbalance of kynurenine to tryptophan ratio in microenvironment was closely related to the resistance for immune checkpoint inhibitor (Li et al, 2019).…”

“…Engel et al. found that serine content of microenvironment determined the growth and survival of glioblastoma ( Engel et al., 2020 ). In lung cancer, the imbalance of kynurenine to tryptophan ratio in microenvironment was closely related to the resistance for immune checkpoint inhibitor ( Li et al., 2019 ).…”