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

Nature
Authors
Keywords
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. 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.

Year of Publication
2015
Journal
Nature
Volume
520
Issue
7547
Pages
363-7
Date Published
2015 Apr 16
ISSN
1476-4687
URL
DOI
10.1038/nature14363
PubMed ID
25855294
PubMed Central ID
PMC4533874
Links
Grant list
R01 CA103866 / CA / NCI NIH HHS / United States
T32 GM007287 / GM / NIGMS NIH HHS / United States
K08-NS087118 / NS / NINDS NIH HHS / United States
R01 CA168653 / CA / NCI NIH HHS / United States
K99 CA168940 / CA / NCI NIH HHS / United States
P30 CA014051 / CA / NCI NIH HHS / United States
T32 GM007753 / GM / NIGMS NIH HHS / United States
K08 NS087118 / NS / NINDS NIH HHS / United States
CA103866 / CA / NCI NIH HHS / United States
AI07389 / AI / NIAID NIH HHS / United States
R01CA168653 / CA / NCI NIH HHS / United States
5P30CA14051 / CA / NCI NIH HHS / United States
T32GM007287 / GM / NIGMS NIH HHS / United States
R37 AI047389 / AI / NIAID NIH HHS / United States
Howard Hughes Medical Institute / United States
CA129105 / CA / NCI NIH HHS / United States
R01 CA129105 / CA / NCI NIH HHS / United States
T32 AI007389 / AI / NIAID NIH HHS / United States