SHMT2 drives glioma cell survival in ischaemia but imposes a dependence on glycine clearance
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SHMT2 drives.pdf
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Author(s)
Kami, Kenjiro
Shelton, Laura M.
Ramkissoon, Shakti H.
Ligon, Keith L.
Snuderl, Matija
Kim, Dohoon
Fiske, Brian Prescott
Birsoy, Kivanc
Freinkman, Elizaveta
Possemato, Richard
Date Issued
April 2015
Journal
Nature
Publisher
Nature Publishing Group
Citation
Kim, Dohoon et al. “SHMT2 Drives Glioma Cell Survival in Ischaemia but Imposes a Dependence on Glycine Clearance.” Nature 520.7547 (2015): 363–367.
Version
Author's final manuscript
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 microenvironment1, 2, 3. 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.
MIT Department
Harvard University--MIT Division of Health Sciences and Technology
Massachusetts Institute of Technology. Department of Biology
Whitehead Institute for Biomedical Research
Koch Institute for Integrative Cancer Research at MIT
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Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
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DOI of Published Version
https://doi.org/10.1038/nature14363
