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NEWS & VIEWS RESEARCH oxidative respiration occurs downstream of providing NADPH and activating antioxidant glycolysis, and so does not compete with gly defence systems. The findings have notable colysis for carbon equivalents and would not implications for understanding the energetic interfere with a high glycolytic flux. Moreover, balance during cancer development: block Glucose unlike respiring cells, which shuffle pyruvate Cytoplasm ing pyruvate kinase to redirect the metabolic from the cytoplasm into the mitochondria — flux is energetically costly under conditions the organelles within which oxidative respi Glycolysis of low respiratory activity because it dimin ration occurs — cancer cells actively excrete ishes the step that is responsible for the net the lactate they generate from pyruvate. This Phosphoenol pyruvate yield of the cellular energy molecule ATP by contradicts the proposal that cancer cells shut Pyruvate glycolysis. This indicates that maintenance of Cancer down respiration to save carbon equivalents kinase the redox balance is more limiting for tumour for biosynthesis. Finally, even some non-can Pyruvate Lactate growth than are energy levels or biosynthetic cerous cells that do not make use of lactate metabolism. (including yeast, T cells and induced pluri Mitochondrion Could this metabolic reconfiguration be potent stem cells) undergo a Warburg-like Oxidative respiration exploited for therapeutic purposes? Poten metabolic restructuring during rapid growth. tially, yes. But targeting a fundamental redox- Anastasiou and colleagues’ results4 bring balancing process must be cancer-cell specific, the redox balance centre stage to explain this Energy otherwise it would heavily damage other metabolic reconfiguration. They show that the metabolically active cell types, including liver glycolytic enzyme pyruvate kinase — a main Pentose Cancer-cell cells, immune cells and neurons. Yet, PKM2, regulator of the Warburg effect — facilitates phosphate ROS proliferation, triose phosphate isomerase, the pentose phos tumour growth by preventing accumulation of pathway cancer growth phate pathway and its associated metabolites ROS, and so avoiding oxidative damage. are not cancer-cell specific. Nevertheless, a In all living cells, ROS leak from the chain Figure 1 | Restructuring cellular metabolism. promising strategy might be to induce ROS of reactions that constitute oxidative respira Glucose is converted to pyruvate by the overload in cancer cells, thereby making them tion, or are generated as by-products of both cytoplasmic process of glycolysis, generating vulnerable to oxidative damage by neutraliz fatty-acid metabolism and biosynthetic redox energy. When oxygen is present, pyruvate enters ing the protective effects of the Warburg effect. reactions. Under normal physiological condi mitochondria, where it generates more energy To develop such strategies it will be essential tions this is not a problem, because ROS levels through the process of oxidative respiration. to pursue comprehensive quantitative and are kept low and in equilibrium with reducing But, in proliferating cells — and under anaerobic qualitative investigations to understand all molecules. In fact, a certain amount of ROS conditions — pyruvate is converted to lactate. the ROS-producing biochemical reactions in is necessary for normal physiology. But if the In cancer and respiring yeast, reduced activity the cancer cell. ■ normal redox balance is disrupted, or ROS of pyruvate kinase, the enzyme that catalyses the final step of glycolysis, mediates redox balance accumulate, oxidation and disturbed bio by activating the pentose phosphate pathway9. Nana-Maria Grüning and Markus Ralser chemical reactions damage macromolecules, Anastasiou et al.4 show that activation of this are at the Max Planck Institute for Molecular ultimately leading to cell death. Therefore, pathway is crucial for cancer cells, and facilitates Genetics, 14195 Berlin, Germany. M.R. is cancer cells rely on a complex anti-oxidative tumour growth by limiting ROS accumulation also in the Department of Biochemistry and machinery that can dynamically supply reduc and, therefore, oxidative stress. Cambridge Systems Biology Centre, University ing equivalents and clear ROS when required3. of Cambridge, Cambridge, CB2 1GA, UK. Pyruvate kinase is a regulator of cellular activation of the pentose phosphate pathway e-mails: [email protected]; anti-oxidative metabolism. Of the four human and its anti-oxidative activity are essential for [email protected] isoforms of this enzyme, PKM2 plays a cru cancer-cell growth (Fig. 1). They report that, 1. Warburg, O. Science 123, 309–314 (1956). cial part in cancer metabolism. Like other in lung cancer cells, oxidation of PKM2 on 2. Hsu, P. P. & Sabatini, D. M. Cell 134, 703–707 metabolic enzymes, PKM2 levels increase in the cysteine amino-acid residue 358 (Cys358) (2008). tumours5. However, this protein has a unique keeps its activity low. This increases both the 3. Cairns, R. A., Harris, I. S. & Mak, T. W. Nature Rev. Cancer 11, 85–95 (2011). regulatory role in that its decreased catalytic concentration of glucose-6-phosphate — the 4. Anastasiou, D. et al. Science http://dx.doi. activity is associated with tumour progression metabolite that connects glycolysis to the oxi org/10.1126/science.1211485 (2011). and the development of the Warburg effect6,7. dative, NADP+-reducing branch of the pentose 5. Bluemlein, K. et al. Oncotarget 2, 393–400 (2011). 6. Hitosugi, T. et al. Sci. Signal. 2, ra73 (2009). When pyruvate kinase activity is low — as phosphate pathway — and flux through the 7. Christofk, H. R. et al. Nature 452, 230–233 (2008). in cancer cells or in respiring yeast — its sub pentose phosphate pathway. 8. Vander Heiden, M. G. et al. Science 329, strate, phosphoenol pyruvate, accumulates8,9. The authors interfered with the pyruvate- 1492–1499 (2010). 9. Grüning, N.-M. et al. Cell Metab. 14, 415–427 This inhibits the glycolytic enzyme triose kinase-triggered activation of the pentose (2011). phosphate isomerase and leads to activation phosphate pathway by increasing PKM2 10. Krüger, A. et al. Antioxid. Redox Signal. 15, 311–324 of a pathway alternative to glycolysis — the activity in the presence of oxidants. To do this, (2011). pentose phosphate pathway9. Increased activ they mutated the enzyme’s Cys358 to a serine ity of this pathway protects against ROS in at residue or used small-molecule activators. This least two ways. First, it provides NADPH, a treatment had remarkable effects on cancer- CORRECTION reducing factor that is required for the activity cell growth. Accumulation of ROS caused In the News & Views article ‘Ageing: of antioxidant enzymes and for the recycling of oxidative damage and slowed the prolifera Generations of longevity’ by Susan E. the anti-oxidant peptide glutathione. NADPH tion of cancer cells both in tissue culture and Mango (Nature 479, 302–303; 2011), it also compensates for the redox imbalance in tumours grafted into immunocompromised was stated that transient exposure of rats caused by increased nucleotide and fatty-acid mice. to a high-sugar/low-protein diet leads to synthesis3. Second, the pentose phosphate These data suggest that inducing the glucose intolerance. This should have read pathway regulates gene expression in favour Warburg effect promotes cancer growth by “transient exposure of rats to a high-sugar/ of adaptation to oxidative stress10. activating the pentose phosphate pathway, high-fat diet leads to glucose intolerance”. Anastasiou and co-workers4 establish that maintaining the balance of redox equivalents, 8 DECEMBER 2011 | VOL 480 | NATURE | 191 © 2011 Macmillan Publishers Limited. All rights reserved.