The DOI matches its Crossref record; 43 of the 44 references it cites were found in a registry or an index.
SHMT2 drives glioma cell survival in ischaemia but imposes a dependence on glycine clearance
Open accessAbstract
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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“Mitochondrial serine hydroxymethyltransferase (SHMT2) is required for cancer cells to adapt to the tumor environment.”
From Hypoxia signaling in cancer: Implications for therapeutic interventions (2023) · cites this paper as [60]
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“SHMT2 also plays a role in redox balance.”
From A review of small-molecule inhibitors of one-carbon enzymes: SHMT2 and MTHFD2 in the spotlight (2021) · cites this paper as [127]
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“Additionally, expression of SHMT2 promotes survival in the ischemic tumor microenvironment in glioma.”
From A review of small-molecule inhibitors of one-carbon enzymes: SHMT2 and MTHFD2 in the spotlight (2021) · cites this paper as [127]
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Metadata
- 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
- Venue
- Nature
- Published
- 2015-04
- Volume
- 520
- Issue
- 7547
- Pages
- 363-367
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- 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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