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

• Published in: Nature (London) 2015-04, Vol.520 (7547), p.363-367
• Main Authors: 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.
• Format: Article
• Language: English
• Subjects: 13/1; 13/106; 13/51; 13/89; 14; 14/63; 140/58; 38; 631/67/1922; 631/67/2327; 631/67/327; Acetone - analogs & derivatives; Acetone - metabolism; Acetone - toxicity; Animals; Brain Neoplasms - blood supply; Brain Neoplasms - enzymology; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Brain tumors; Cancer; Cancer cells; Carbon; Cell Hypoxia; Cell Line, Tumor; Cell Survival; Enzymes; Female; Glioblastoma - blood supply; Glioblastoma - enzymology; Glioblastoma - metabolism; Glioblastoma - pathology; Gliomas; Glycine; Glycine - metabolism; Glycine Dehydrogenase (Decarboxylating) - antagonists & inhibitors; Glycine Dehydrogenase (Decarboxylating) - metabolism; Glycine Hydroxymethyltransferase - metabolism; Health aspects; Humanities and Social Sciences; Humans; Hypoxia; Ischemia; Ischemia - enzymology; Ischemia - metabolism; Ischemia - pathology; Kinases; letter; Metabolism; Metabolites; Mice; multidisciplinary; Necrosis; Oxygen Consumption; Physiological aspects; Pyruvaldehyde - metabolism; Pyruvaldehyde - toxicity; Pyruvate Kinase - metabolism; Science; Survival; Tumor Microenvironment; Xenograft Model Antitumor Assays
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature14363

Tumours are a low-oxygen environment, in this study glioblastoma cells are found to overexpress the serine hydroxymethyltransferase SHMT2; SHMT acts to reduce oxygen consumption, which confers the tumour cells with a survival advantage. Low oxygen gives tumour cells an edge Tumour cells thrive in a low-oxygen environment, and in this study David Sabatini and colleagues demonstrate a mechanism that operates in the ischaemic zone of glioblastoma cells to give tumour cells a survival advantage. Glioblastoma cells are shown to overexpress the serine hydroxymethyltransferase (SHMT2) and glycine decarboxylase (GLDC). SHMT2 favours poorly vascularized tumour cells by reducing oxygen consumption but at the same time it exposes a selective vulnerability. Glycine, the product of SHMT2 activity, if allowed to accumulate in excess within the cell can be converted into toxic molecules, hence it may be possible to target tumorigenic glioblastoma cells by inhibiting GLDC. 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 , 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.