Observed in cancer (6, 7). The Warburg impact has been proposed to support the proliferative demands of cancer cells (2). In accordance, we showed that PFKFB3 straight contributes towards the proliferation price of MEF cells, specifically within the absence of PTEN. Tudzarova et al. (27) showed that PFKFB3 silencing prevents G1/S transition from the cell cycle by down-regulating glycolytic flux at a nutrientsensitive restriction point. Interestingly, PTEN KO embryonic stem cells have been reported to possess accelerated G1/S transition (28). It would thus be interesting to investigate no matter if PTEN-deficient cells exploit their elevated PFKFB3 protein levels to bypass the G1/S restriction point and accelerate their progression by means of the cell cycle. Moreover, the therapeutic prospective of targeting PFKFB3 and F2,6P2 as metabolic mediators of proliferation in PTEN-deficient cancers is worthy of consideration.Acknowledgments–We thank Dr. Tak Mak (University of Toronto) for providing wild-type and PTEN-deficient MEF cells, Dr. Richard Honzatko (Iowa State University) for the generous gift of F2,6P2 standard, and Drs. William Hahn, William Sellers, and Marc Kirschner for delivering DNA plasmids. We also thank Natalie Weili Ng, Dr. Istvan Kovacs, and Prof. Salvador Moncada for their help with the experiments for the revision.ten. Kohn, A. D., Summers, S. A., Birnbaum, M. J., and Roth, R. A. (1996) Expression of a constitutively active Akt Ser/Thr kinase in 3T3-L1 adipocytes stimulates glucose uptake and glucose transporter 4 translocation. J. Biol. Chem. 271, 31372?1378 11. Deprez, J., Vertommen, D., Alessi, D. R., Hue, L., and Rider, M. H. (1997) Phosphorylation and activation of heart 6-phosphofructo-2-kinase by protein kinase B and also other protein kinases from the insulin signaling cascades. J. Biol. Chem. 272, 17269 ?7275 12. Gottlob, K., Majewski, N., Kennedy, S., Kandel, E., Robey, R.2387561-40-0 Chemical name B., and Hay, N. (2001) Inhibition of early apoptotic events by Akt/PKB is dependent on the very first committed step of glycolysis and mitochondrial hexokinase. Genes Dev. 15, 1406 ?418 13. Elstrom, R. L., Bauer, D. E., Buzzai, M., Karnauskas, R., Harris, M. H., Plas, D. R., Zhuang, H., Cinalli, R. M., Alavi, A., Rudin, C. M., and Thompson, C. B. (2004) Akt stimulates aerobic glycolysis in cancer cells. Cancer Res. 64, 3892?899 14. Song, M. S., Carracedo, A., Salmena, L., Song, S. J., Egia, A., Malumbres, M., and Pandolfi, P. P. (2011) Nuclear PTEN regulates the APC-CDH1 tumor-suppressive complicated within a phosphatase-independent manner. Cell 144, 187?99 15. Li, M., and Zhang, P. (2009) The function with the APC/CCdh1 in cell cycle and beyond.2223047-95-6 web Cell Division four, 2 16.PMID:32472497 Herrero-Mendez, A., Almeida, A., Fern dez, E., Maestre, C., Moncada, S., and Bola s, J. P. (2009) The bioenergetic and antioxidant status of neurons is controlled by continuous degradation of a important glycolytic enzyme by APC/C-Cdh1. Nat. Cell Biol. 11, 747?52 17. Almeida, A., Bola s, J. P., and Moncada, S. (2010) E3 ubiquitin ligase APC/C-Cdh1 accounts for the Warburg effect by linking glycolysis to cell proliferation. Proc. Natl. Acad. Sci. U.S.A. 107, 738 ?41 18. Hue, L., and Rider, M. H. (1987) Function of fructose 2,6-bisphosphate within the handle of glycolysis in mammalian tissues. Biochem. J. 245, 313?24 19. Yalcin, A., Telang, S., Clem, B., and Chesney, J. (2009) Regulation of glucose metabolism by 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases in cancer. Exp. Mol. Pathol. 86, 174 ?79 20. Van Schaftingen, E., Leder.