Cited by 372Cancer, Hypoxia, and MetabolismGlioma Diagnosis and TreatmentAmino Acid Enzymes and Metabolism

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

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Kim, Dohoon, Fiske, Brian P., Birsoy, Kivanc, Freinkman, Elizaveta, Kami, Kenjiro, Possemato, Richard L., Chudnovsky, Yakov, Pacold, Michael E., Chen, Walter W., Cantor, Jason R., Shelton, Laura M., Gui, Dan Y., Kwon, Manjae, Ramkissoon, Shakti H., Ligon, Keith L., Kang, Seong Woo, Snuderl, Matija, Vander Heiden, Matthew G., Sabatini, David M.·2015·Nature

DOI 10.1038/nature14363PMC PMC4533874

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Abstract

Cancer 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 tumour microenvironment. Here we identify a key role for serine and glycine metabolism in the survival of brain cancer cells within the ischaemic zones of gliomas. In human glioblastoma multiforme, 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 tumour 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 tumour environment, but also renders these cells sensitive to glycine cleavage system inhibition.

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Authors: Kim, D., Fiske, B. P., Birsoy, K., Freinkman, E., Kami, K., Possemato, R. L., Chudnovsky, Y., Pacold, M. E., Chen, W. W., Cantor, J. R., Shelton, L. M., Gui, D. Y., Kwon, M., Ramkissoon, S. H., Ligon, K. L., Kang, S. W., Snuderl, M., Vander Heiden, M. G., & Sabatini, D. M.
Affiliations: Broad Institute (US)
Human Metabolome Technologies, Inc. (Japan) (JP)
Whitehead Institute for Biomedical Research (US)
Brigham and Women's Hospital (US)
NYU Langone Health (US)
Corresponding author: Sabatini, David M.
ORCID: Kim, Dohoon
Fiske, Brian P.
Possemato, Richard L.
Pacold, Michael E.
Chen, Walter W.
Cantor, Jason R.
Shelton, Laura M.
Gui, Dan Y.
Kwon, Manjae
Ligon, Keith L.
Snuderl, Matija
Sabatini, David M.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2015-04
Volume: 520
Issue: 7547
Pages: 363-367
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature14363
PMC: PMC4533874
OpenAlex: W1993238514
Cited by: 368
References: 44
Citations by year: 2026: 25 · 2025: 22 · 2024: 21 · 2023: 28 · 2022: 41 · 2021: 42 · 2020: 25 · 2019: 39 · 2018: 34 · 2017: 30 · 2016: 42 · 2015: 18
FWCI: 13.77
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
RePEc: Research Papers in Economics (submittedVersion)
DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
Radboud Repository (Radboud University) (submittedVersion)
PMC
Funders: Howard Hughes Medical Institute
National Cancer Institute (5-P30-CA14051, CA129105, K99CA168940, CA103866, R01CA103866, R01CA168653, R01CA129105, R00CA168940, P30CA014051)
National Institute of General Medical Sciences (T32GM007753, T32GM007287)
National Institute of Allergy and Infectious Diseases (AI-07389, T32AI007389, R37AI047389)
National Institute of Neurological Disorders and Stroke (K08NS087118)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Health Sciences › Medicine › Oncology › Glioma Diagnosis and Treatment
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
Keywords: SHMT2, glycine decarboxylase, glioblastoma, serine metabolism, glycine metabolism, oxygen consumption, PKM2, methylglyoxal, aminoacetone, tumor cell survival, tumor hypoxia
MeSH terms: Acetone, Animals, Brain Neoplasms, Cell Survival, Female, Glioblastoma, Glycine, Humans, Ischemia, Necrosis, Oxygen Consumption, Pyruvaldehyde, Pyruvate Kinase, Glycine Hydroxymethyltransferase, Cell Hypoxia, Xenograft Model Antitumor Assays, Cell Line, Tumor, Glycine Dehydrogenase (Decarboxylating), Mice, Tumor Microenvironment

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

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