SHMT2 drives glioma cell survival in ischaemia but imposes a dependence on glycine clearance
| Autor: | Dohoon Kim, Jason R. Cantor, Matija Snuderl, Keith L. Ligon, David M. Sabatini, Brian P. Fiske, Manjae Kwon, Richard Possemato, Dan Y. Gui, Elizaveta Freinkman, Michael E. Pacold, Yakov Chudnovsky, Laura M. Shelton, Kıvanç Birsoy, Walter W. Chen, Matthew G. Vander Heiden, Kenjiro Kami, Shakti Ramkissoon, Seong Woo Anthony Kang |
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| Rok vydání: | 2015 |
| Předmět: |
Cell Survival
Pyruvate Kinase Glycine PKM2 Biology Article Acetone Serine Mice Necrosis Oxygen Consumption Ischemia Cell Line Tumor Tumor Microenvironment Animals Humans Glycine Hydroxymethyltransferase Tumor microenvironment Multidisciplinary Glycine cleavage system Brain Neoplasms Glycine Dehydrogenase (Decarboxylating) Pyruvaldehyde Xenograft Model Antitumor Assays Cell Hypoxia 3. Good health Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11] Biochemistry Cell culture Serine hydroxymethyltransferase Cancer cell Cancer research Female Glioblastoma |
| Zdroj: | Nature, 520, 7547, pp. 363-7 Nature, 520, 363-7 Nature |
| ISSN: | 0028-0836 |
| Popis: | Item does not contain fulltext 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. |
| Databáze: | OpenAIRE |
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