1. SHMT2 drives glioma cell survival in ischaemia but imposes a dependence on glycine clearance
- Author
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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, Heiden, Matthew G. Vander, and Sabatini, David M.
- Subjects
Ischemia -- Physiological aspects ,Gliomas -- Physiological aspects ,Glycine -- Health aspects ,Cancer cells -- Health aspects ,Environmental issues ,Science and technology ,Zoology and wildlife conservation - 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 (1-3). 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., Many inborn disorders of amino acid metabolism lead to severe impairment of the developing nervous system, at least in part through toxic effects on neural stem cells (4,5). As brain [...]
- Published
- 2015