CBMS-07 SERINE SYNTHESIS AND ONE-CARBON METABOLISM IN GLIOMA CELLS TO SURVIVE GLUTAMINE STARVATION

Abstract

Cancer cells optimize nutrient utilization to supply energetic and biosynthetic pathways. These metabolic processes also include redox maintenance and epigenetic regulation through nucleic acid and protein methylation, enhancing tumorigenicity and clinical resistance. But less is known about how cancer cells exhibit metabolic flexibility to sustain cell growth and survival from nutrient starvation. Here, we identify a key role for serine availability and one-carbon metabolism in the survival of glioma cells from glutamine deprivation. To identify metabolic response to glutamine deprivation in glioma cells, we analyzed metabolites using gas chromatography and mass spectroscopy (GC/MS) in glioma cells cultured in glutamine-deprived medium and examined gene expression of key enzymes for one-carbon units using RT-PCR and western blotting methods. These expressions were also confirmed by immunohistochemical staining in glioma clinical samples Metabolome studies indicated serine, cysteine, and methionine as key differentiating amino acids between control and glutamine-deprived groups. Serine synthesis was mediated through autophagy rather than glycolysis. Gene expression analysis identified upregulation of Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) to regulate serine synthesis and one-carbon metabolism. Importantly, suppression of this metabolite impaired glioma cell survival in glutamine deprivation. In human glioma samples. MTHFD2 expressions were highest in poorly nutrient regions around “pseudopalisading necrosis”. Serine-dependent one-carbon metabolism has a key role for glioma cells to survive glutamine starvation. These results may suggest the new therapeutic strategies targeting critical glioma cells adapting the tumor microenvironment.