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Gluconeogenesis in Cancer: Door Wide Open

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Gluconeogenesis in Cancer: Door Wide Open LETTER Gluconeogenesis in cancer: Door wide open Zhang et al. (1) make a valuable contribution activated in lung cancer cells under low aDivision of Pulmonology, Department of to the field of cancer metabolism, showing glucose and mediates conversion of lactate Internal Medicine, Medical University of Graz, that the tumor suppressor p53 down-regu- to phosphoenolpyruvate (3). However, we A-8036 Graz, Austria; and bLudwig lates the gluconeogenic key enzyme phospho- found that in lung cancer cells and in tumor Boltzmann Institute for Lung Vascular enolpyruvate carboxykinase (PEPCK, PCK1) samples PCK2 (PEPCK-M), the mitochon- Research, A-8036 Graz, Austria via histone deacetylase sirtuin 6. The authors drial isoform of the enzyme, and not PCK1, conclude that inhibition of gluconeogenesis the cytoplasmic isoform (PEPCK-C) studied may contribute to the tumor-suppressive by Zhang et al. (1), was expressed at high 1 Zhang P, et al. (2014) Tumor suppressor p53 cooperates with function of p53. Gluconeogenesis, a reverse levels. We further demonstrated that PCK2 SIRT6 to regulate gluconeogenesis by promoting FoxO1 nuclear exclusion. Proc Natl Acad Sci USA 111(29):10684–10689. glycolysis pathway, generates glucose from limits cancer cell death under low glucose 2 Schulze A, Harris AL (2012) How cancer metabolism is tuned for small carbohydrate precursors. The authors conditions and in 3D spheroids (3). Similar proliferation and vulnerable to disruption. Nature 491(7424):364–373. speculate that this is conceivably essential findings on PCK2 were obtained in breast, 3 Leithner K, et al. (2014) PCK2 activation mediates an adaptive response to glucose depletion in lung cancer. Oncogene, 10.1038/onc.2014.47. for tumor cell growth (1). Biosynthetic reac- cervical, and colon carcinoma cells and 4 Méndez-Lucas A, Hyrossová P, Novellasdemunt L, Viñals F, tions in cancer cells are highly dependent on publishedthisyearaswell(4).Thus, Perales JC (2014) Mitochondrial phosphoenolpyruvate carboxykinase glycolysis intermediates (2). In fact, PEPCK PEPCKseemstoplayanimportantrole (PEPCK-M) is a pro-survival, endoplasmic reticulum (ER) stress response gene involved in tumor cell adaptation to nutrient has a unique position in cell metabolism, in cancer cells, especially under glucose lim- availability. J Biol Chem 289(32):22090–22102. allowing the conversion of small carbon itation. Because PCK2 (mitochondrial 5 Stark R, Kibbey RG (2014) The mitochondrial isoform of phosphoenolpyruvate carboxykinase (PEPCK-M) and glucose homeostasis: metabolites and tricarboxylic acid cycle PEPCK) is more widely expressed in hu- Has it been overlooked? Biochim Biophys Acta 1840(4):1313–1330. metabolites into glycolysis intermediates. man tissues when compared with PCK1 Still, PEPCK was not considered in cancer (5), PCK2 might have an even broader sig- research, possibly because of its main func- nificance in cancers than PCK1. Author contributions: K.L., A.H., and H.O. wrote the paper. tion in specialized tissues, such as the liver. a,1 a,b The authors declare no conflict of interest. Recently, our group showed, for the first Katharina Leithner ,AndelkoHrzenjak , 1 a To whom correspondence should be addressed. Email: katharina. time to our knowledge, that PEPCK is and Horst Olschewski [email protected]. E4394 | PNAS | October 21, 2014 | vol. 111 | no. 42 www.pnas.org/cgi/doi/10.1073/pnas.1415680111 Downloaded by guest on September 24, 2021.
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