Nature 520, 363–367 (2015)

Credit: Nature

Glioblastoma multiforme (GBM) is one of the most aggressive brain tumors and is characterized histologically by the presence of a necrotic center surrounded by a band of viable tumor cells that make up a structure called pseudopalisades. Despite their lack of access to oxygen and nutrients, these cells are able to thrive and proliferate. To identify the metabolic alterations in GBM tumors that allow survival under these hypoxic conditions, Kim et al. compared the expression of metabolic genes between human GBM and normal brain tissues and found that genes involved in glycine metabolism had elevated expression in patients with GBM. In particular, pseudopalisades expressed high levels of mitochondrial serine hydroxymethyltransferase (SHMT2), an enzyme that converts serine to glycine. SHMT2 was confirmed as an essential determinant for hypoxic cell survival, as SHMT2 knockdown in an xenograft model of GBM resulted in cell death. To identity the metabolic changes induced by SHMT2 that allow survival, the authors examined metabolic changes that occur when a GBM cell line (LN229) loses SHMT2 expression. They detected elevated levels of serine and fructose bisphosphate (FBP), which are known to activate pyruvate kinase isoform 2 (PKM2), which stimulates pyruvate production during glycolysis. SHMT2 knockdown boosted PKM2 metabolic activity, resulting in increased TCA cycle activity and oxygen consumption. Treatment of LN229 cells with small-molecule activators of PKM2 decreased LN229 hypoxic survival through increased oxygen consumption. In addition to having reduced PKM2 activity, cells with elevated SHMT2 expression produced large amounts of glycine that needed to be degraded into ammonia and carbon dioxide by glycine decarboxylase (GLDC). Knockdown of GLDC reduced LN229 viability by promoting glycine metabolism by glycine C-acetyltransferase, resulting in the formation of the toxic byproducts amino-acetone and methylglyoxal. Overall, these findings may inspire new ways to modulate glycine metabolism for potential treatment of GBMs.