Glioma cells require one-carbon metabolism to survive glutamine starvation

Kazuhiro Tanaka, Takashi Sasayama, Hiroaki Nagashima, Yasuhiro Irino, Masatomo Takahashi, Yoshihiro Izumi, Takiko Uno, Naoko Satoh, Akane Kitta, Katsusuke Kyotani, Yuichi Fujita, Mitsuru Hashiguchi, Tomoaki Nakai, Masaaki Kohta, Yoichi Uozumi, Masakazu Shinohara, Kohkichi Hosoda, Takeshi Bamba, Eiji Kohmura

Research output: Contribution to journalArticlepeer-review


Cancer cells optimize nutrient utilization to supply energetic and biosynthetic pathways. This metabolic process also includes redox maintenance and epigenetic regulation through nucleic acid and protein methylation, which enhance tumorigenicity and clinical resistance. However, less is known about how cancer cells exhibit metabolic flexibility to sustain cell growth and survival from nutrient starvation. Here, we find that serine and glycine levels were higher in low-nutrient regions of tumors in glioblastoma multiforme (GBM) patients than they were in other regions. Metabolic and functional studies in GBM cells demonstrated that serine availability and one-carbon metabolism support glioma cell survival following glutamine deprivation. Serine synthesis was mediated through autophagy rather than glycolysis. Gene expression analysis identified upregulation of methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) to regulate one-carbon metabolism. In clinical samples, MTHFD2 expression was highest in the nutrient-poor areas around “pseudopalisading necrosis.” Genetic suppression of MTHFD2 and autophagy inhibition caused tumor cell death and growth inhibition of glioma cells upon glutamine deprivation. These results highlight a critical role for serine-dependent one-carbon metabolism in surviving glutamine starvation and suggest new therapeutic targets for glioma cells adapting to a low-nutrient microenvironment.

Original languageEnglish
Article number16
JournalActa neuropathologica communications
Issue number1
Publication statusPublished - Dec 2021

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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