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

Nature. 2015 Apr 16;520(7547):363-7. doi: 10.1038/nature14363. Epub 2015 Apr 8.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetone / analogs & derivatives
  • Acetone / metabolism
  • Acetone / toxicity
  • Animals
  • Brain Neoplasms / blood supply
  • Brain Neoplasms / enzymology
  • Brain Neoplasms / metabolism*
  • Brain Neoplasms / pathology*
  • Cell Hypoxia
  • Cell Line, Tumor
  • Cell Survival
  • Female
  • Glioblastoma / blood supply
  • Glioblastoma / enzymology
  • Glioblastoma / metabolism*
  • Glioblastoma / pathology*
  • Glycine / metabolism*
  • Glycine Dehydrogenase (Decarboxylating) / antagonists & inhibitors
  • Glycine Dehydrogenase (Decarboxylating) / metabolism
  • Glycine Hydroxymethyltransferase / metabolism*
  • Humans
  • Ischemia / enzymology
  • Ischemia / metabolism*
  • Ischemia / pathology
  • Mice
  • Necrosis
  • Oxygen Consumption
  • Pyruvaldehyde / metabolism
  • Pyruvaldehyde / toxicity
  • Pyruvate Kinase / metabolism
  • Tumor Microenvironment
  • Xenograft Model Antitumor Assays


  • Acetone
  • Pyruvaldehyde
  • Glycine Dehydrogenase (Decarboxylating)
  • Glycine Hydroxymethyltransferase
  • Pyruvate Kinase
  • Glycine
  • aminoacetone