SHMT2 Drives Ischemic Glioma Cell Survival and Sensitivity to Excess Glycine

Metabolic adaptation supports increased proliferation and is a hallmark of cancer cells, but it is unclear whether deregulated metabolism plays a similar role in poorly vascularized tumor areas. Kim and colleagues identified amino acid catabolism genes that were both required for neural stem cell proliferation and upregulated in glioma, including glycine decarboxylase (GLDC), which encodes a component of the glycine cleavage complex. Suppression of GLDC inhibited the viability and neurosphere formation of undifferentiated, but not differentiated, glioblastoma cell lines and increased intracellular levels of glycine, which, when added exogenously, promoted toxicity in a dose-dependent manner. Suppression of glycine C-acetyltransferase (GCAT) reversed the antiproliferative effects of GLDC depletion, suggesting that GCAT-mediated conversion of glycine into harmful metabolites may drive cell toxicity. Indeed, GLDC depletion led to a GCAT-dependent increase in aminoacetone and methylglyoxal levels, and suppression of serine hydroxymethyltransferase (SHMT2), an upstream mitochondrial enzyme that converts serine to glycine, had a similar protective effect against GLDC knockdown. In further support of a synthetic lethal relationship between SHMT2 and glycine clearance, increased SHMT2 expression correlated with sensitivity to GLDC inhibition in cancer cell lines. High levels of SHMT2 and GLDC were detected in glioblastoma pseudopalisading cells surrounding necrotic areas, and overexpression of SHMT2 had a protective effect on glioblastoma cells under hypoxic conditions both in vitro and in vivo. Quantitative metabolic profiling revealed that SHMT2 suppression increased the levels of activators of pyruvate kinase isoform M2 (PKM2) and enhanced PKM2 flux, providing a survival advantage under ischemia. Consistent with this idea, forced PKM2 expression increased oxygen consumption and reduced glioblastoma cell survival under hypoxic conditions in vitro and in vivo. Together, this data suggests that SHMT2 upregulation promotes cancer cell survival in the ischemic tumor microenvironment by inducing metabolic rewiring and that GLDC inhibition may be used to specifically target these cells.

Kim D, Fiske BP, Birsoy K, Freinkman E, Kami K, Possemato RL, et al. SHMT2 drives glioma cell survival in ischaemia but imposes a dependence on glycine clearance. Nature 2015;520:363–7.

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