SignificancePhosphoenolpyruvate carboxykinase (PEPCK) has a unique position in cell metabolism by allowing the flexible use of nutrients for anabolic biosynthetic reactions. PEPCK activity has just recently been described in cancer cells. It has been shown to promote cancer cell survival under nutrient deprivation, a typical feature in solid cancers, as well as cancer growth. To decipher the metabolic downstream pathways of PEPCK is critical for a better understanding of cancer cell adaptive responses under low nutrient stress. Here, we show that mitochondrial PEPCK (PEPCK-M) mediates the synthesis of glycerol phosphate from noncarbohydrate precursors, and that PEPCK-M is needed to maintain levels of glycerophospholipids, major constituents of biomembranes, in starved lung cancer cells.

glycolysis and gluconeogenesis are activated in NSCLC in a tumor size and oxygenation modulated manner and differentially correlate with outcome. The frequent co-activation of gluconeogenesis and glycolysis in NSCLC should be considered in potential future therapeutic strategies targeting cancer cell metabolism.

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