Gluconeogenesis in cancer: Door wide open

Zhang et al. (1) make a valuable contribution to the field of cancer metabolism, showing that the tumor suppressor p53 down-regulates the gluconeogenic key enzyme phosphoenolpyruvate carboxykinase (PEPCK, PCK1) via histone deacetylase sirtuin 6. The authors conclude that inhibition of gluconeogenesis may contribute to the tumor-suppressive function of p53. Gluconeogenesis, a reverse glycolysis pathway, generates glucose from small carbohydrate precursors. The authors speculate that this is conceivably essential for tumor cell growth (1). Biosynthetic reactions in cancer cells are highly dependent on glycolysis intermediates (2). In fact, PEPCK has a unique position in cell metabolism, allowing the conversion of small carbon metabolites and tricarboxylic acid cycle metabolites into glycolysis intermediates. Still, PEPCK was not considered in cancer research, possibly because of its main function in specialized tissues, such as the liver. Recently, our group showed, for the first time to our knowledge, that PEPCK is activated in lung cancer cells under low glucose and mediates conversion of lactate to phosphoenolpyruvate (3). However, we found that in lung cancer cells and in tumor samples PCK2 (PEPCK-M), the mitochondrial isoform of the enzyme, and not PCK1, the cytoplasmic isoform (PEPCK-C) studied by Zhang et al. (1), was expressed at high levels. We further demonstrated that PCK2 limits cancer cell death under low glucose conditions and in 3D spheroids (3). Similar findings on PCK2 were obtained in breast, cervical, and colon carcinoma cells and published this year as well (4). Thus, PEPCK seems to play an important role in cancer cells, especially under glucose limitation. Because PCK2 (mitochondrial PEPCK) is more widely expressed in human tissues when compared with PCK1 (5), PCK2 might have an even broader significance in cancers than PCK1.