Cancer cells are reprogrammed to consume large amounts of
glucose to support anabolic biosynthetic pathways. However, blood perfusion and consequently the supply with
glucose are frequently inadequate in solid
cancers. PEPCK-M (PCK2), the mitochondrial
isoform of
phosphoenolpyruvate carboxykinase (PEPCK), has been shown by us and others to be functionally expressed and to mediate gluconeogenesis, the reverse pathway of glycolysis, in different
cancer cells.
Serine and
ribose synthesis have been identified as downstream pathways fed by PEPCK in
cancer cells. Here, we report that PEPCK-M-dependent
glycerol phosphate formation from noncarbohydrate precursors (glyceroneogenesis) occurs in starved
lung cancer cells and supports de novo
glycerophospholipid synthesis. Using stable
isotope-labeled
glutamine and
lactate, we show that PEPCK-M generates
phosphoenolpyruvate and
3-phosphoglycerate, which are at least partially converted to
glycerol phosphate and incorporated into
glycerophospholipids (GPL) under
glucose and serum
starvation. This pathway is required to maintain levels of GPL, especially
phosphatidylethanolamine (PE), as shown by stable
shRNA-mediated silencing of PEPCK-M in H23
lung cancer cells. PEPCK-M
shRNA led to reduced colony formation after
starvation, and the effect was partially reversed by the addition of dioleyl-PE. Furthermore, PEPCK-M silencing abrogated
cancer growth in a
lung cancer cell xenograft model. In conclusion,
glycerol phosphate formation for de novo GPL synthesis via glyceroneogenesis is a newly characterized anabolic pathway in
cancer cells mediated by PEPCK-M under conditions of severe nutrient deprivation.