SHMT2 drives glioma cell survival in ischaemia but imposes a dependence on glycine clearance

Abstract

SUMMARYCancer cells adapt their metabolic processes to support rapid proliferation, but less is known about how cancer cells alter metabolism to promote cell survival in a poorly vascularized tumor microenvironment1–3. Here, we identify a key role for serine and glycine metabolism in the survival of brain cancer cells within the ischemic zones of gliomas. In human glioblastoma multiforme (GBM), mitochondrial serine hydroxymethyltransferase (SHMT2) and glycine decarboxylase (GLDC) are highly expressed in the pseudopalisading cells that surround necrotic foci. We find that SHMT2 activity limits that of pyruvate kinase (PKM2) and reduces oxygen consumption, eliciting a metabolic state that confers a profound survival advantage to cells in poorly vascularized tumor regions. GLDC inhibition impairs cells with high SHMT2 levels as the excess glycine not metabolized by GLDC can be converted to the toxic molecules aminoacetone and methylglyoxal. Thus, SHMT2 is required for cancer cells to adapt to the tumor environment, but also renders these cells sensitive to glycine cleavage system inhibition.

Targeting MTHFD2 in acute myeloid leukemia

“…In the same year, glycine decarboxylase and other glycine/serine-related enzymes, including SHMT2, were found to promote cellular transformation and tumorigenesis in lung cancer models (Zhang et al, 2012). Additionally, SHMT2 was found to drive glioma cell proliferation in the presence of ischemia, making the cells sensitive to inhibition of the glycine cleavage system (Kim et al, 2015). In an analysis of differentially expressed mRNA in cancer tissues, Nilsson et al (2014) identified enzymes of the one-carbon folate pathway to be among the most differentially expressed metabolic enzymes in cancer compared with normal cells, with MTH FD2 ranking at the top of the list.…”

“…Heiden et al, 2010). Additionally, the discovery of the critical importance of glycine and serine in cancer metabolism has led to a resurgence in interest in better understanding the mechanistic relevance of one-carbon folate metabolism (Jain et al, 2012;Zhang et al, 2012;Labuschagne et al, 2014;Kim et al, 2015;Maddocks et al, 2016).…”

Suppression of MTHFD2 in MCF-7 Breast Cancer Cells Increases Glycolysis, Dependency on Exogenous Glycine, and Sensitivity to Folate Depletion

“…Serine is a direct ligand and allosteric activator of PKM2 22 , and it was recently reported that suppression of the mitochondrial enzyme SHMT2 upstream of MTHFD2 limits the activity of the PKM2 in glioma cells by decreasing the levels of its metabolic activators 23 . Increased intracellular serine levels due to disruption of mitochondrial glycine synthesis with MTHFD2 suppression may therefore potentially be responsible for the more glycolytic phenotype observed.…”

The effect of neurosphere culture conditions on the cellular metabolism of glioma cells

“…Detection and targeting of miss-regulated choline-, myo-inositol-, creatine-, and glycine-metabolism has been de scribed to have potential utility in the diagnosis and treatment of malignant gliomas [2][3][4]13,16,19]. This is, to our knowledge, the hitherto first link of changes in those oncometabolites [4,25] to variations in cell culture conditions of glioma cells.…”

“…Glycine (Gly), a currently intensively studied me tabolite with oncogenic potential, has been re ported to be directly correlated with glioma malignancy [4]. Hypoxic glioma cells, which are known to contain a population of cells with high stem-like signature [11], are highly susceptible to glycine metabolism [13]. In addition, efforts using 1 H-NMR-spectroscopy to grade brain tumour malignancy based on their cellular metabolism suggested glycine as a negative prognostic biomarker [5,17,22].…”