Abstract

The high rate of glucose breakdown is the fingerprint of cancer. Increased glycolysis allows tumour cells to fulfil their high energetic and biosynthetic demands. Interestingly, however, rather than metabolizing glucose in the oxidative phosphorylation pathway, cancer cells generally use glucose for aerobic glycolysis. This phenomenon is known as the Warburg effect and is considered as one of the most fundamental forms of metabolic reprogramming during cancerogenesis. Changes in the rate of glycolytic activity of cancer cells are caused mainly by the increased expression of glycolytic enzymes as a consequence of activation of oncogenes or loss of tumour suppressors. In addition, the hypoxic tumour environment also triggers upregulation of a series of genes involved in glucose metabolism. Among the metabolic enzymes that are modulated by these factors in cancer cells are the 6-phosphofructo 2-kinase/fructose 2,6-bisphosphatases (PFKFBs), a family of bifunctional enzymes that control the levels of fructose 2,6-bisphosphate (Fru-2,6-P2), an essential activator of the glycolytic flux. Fru-2,6-P2 strongly activates glucose breakdown in glycolysis through allosteric modulation of the rate-limiting enzyme of glycolysis, phosphofructokinase-1 (PFK-1). Thus far, many studies have reported a correlation between aberrant PFKFB expression level and the grade of tumour aggressiveness, which directly indicates that these enzymes may play a crucial role in cancerogenesis. The objective of this review is to highlight the recent studies on aberrant expression of PFKFBs and its influence on cancer progression.

References

• 1. Akashi M., Shaw G., Hachiya M., Elstner E., Suzuki G., Koeffler P.:Number and location of AUUUA motifs: role in regulating transientlyexpressed RNAs. Blood, 1994; 83: 3182-3187
  Google Scholar
• 2. Al Hasawi N., Alkandari M.F., Luqmani Y.A.: Phosphofructokinase:a mediator of glycolytic flux in cancer progression. Crit. Rev. Oncol.Hematol., 2014; 92: 312-321
  Google Scholar
• 3. Almeida A., Bolanos J.P., Moncada S.: E3 ubiquitin ligase APC/C–Cdh1 accounts for the Warburg effect by linking glycolysis to cellproliferation. Proc. Natl. Acad. Sci. USA, 2010; 107: 738-741 4 Altenberg B., Greulich K.O.: Genes of glycolysis are ubiquitouslyoverexpressed in 24 cancer classes. Genomics, 2004; 84: 1014-1020
  Google Scholar
• 4. (PFKFB4) is required forthe glycolytic response to hypoxia and tumor growth. Oncotarget,2014; 5: 6670-6686
  Google Scholar
• 5. Atsumi T., Chesney J., Metz C., Leng L., Donnelly S., Makita Z.,Mitchell R., Bucala R.: High expression of inducible 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase(iPFK-2; PFKFB3) in humancancers. Cancer Res., 2002; 62: 5881-5887
  Google Scholar
• 6. Baek D., Davis C., Ewing B., Gordon D., Green P.: Characterizationand predictive discovery of evolutionarily conserved mammalianalternative promoters. Genome Res., 2007; 17: 145-155
  Google Scholar
• 7. Bando H., Atsumi T., Nishio T., Niwa H., Mishima S., ShimizuC., Yoshioka N., Bucala R., Koike T.: Phosphorylation of the 6-phosphofructo-2-kinase/fructose2,6-bisphosphatase/PFKFB3 familyof glycolytic regulators in human cancer. Clin. Cancer Res., 2005;11: 5784-5792
  Google Scholar
• 8. Bartrons R., Caro J.: Hypoxia, glucose metabolism and the Warburg’seffect. J. Bioenerg. Biomembr., 2007; 39: 223-229
  Google Scholar
• 9. Bertrand L., Alessi D.R., Deprez J., Deak M., Viaene E., Rider M.H.,Hue L.: Heart 6-phosphofructo-2-kinase activation by insulin resultsfrom Ser-466 and Ser-483 phosphorylation and requires 3-phosphoinositide-dependentkinase-1, but not protein kinase B. J. Biol.Chem., 1999; 274: 30927-30933
  Google Scholar
• 10. Bobarykina A.Y., Minchenko D.O., Opentanova I.L., Moenner M.,Caro J., Esumi H., Minchenko O.H.: Hypoxic regulation of PFKFB-3and PFKFB-4 gene expression in gastric and pancreatic cancer cell lines and expression of PFKFB genes in gastric cancers. Acta Biochim.Pol., 2006; 53: 789-799
  Google Scholar
• 11. Calvo M.N., Bartrons R., Castano E., Perales J.C., Navarro-SabateA., Manzano A.: PFKFB3 gene silencing decreases glycolysis, inducescell-cycle delay and inhibits anchorage-independent growth in HeLacells. FEBS Lett., 2006; 580: 3308-3314
  Google Scholar
• 12. Cantor J.R., Sabatini D.M.: Cancer cell metabolism: one hallmark,many faces. Cancer Discov., 2012; 2: 881-898
  Google Scholar
• 13. Chesney J., Clark J., Klarer A.C., Imbert-Fernandez Y., Lane A.N.,Telang S.: Fructose-2,6-bisphosphate synthesis by 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase
  Google Scholar
• 14. Chesney J., Mitchell R., Benigni F., Bacher M., Spiegel L., Al-AbedY., Han J.H., Metz C., Bucala R.: An inducible gene product for 6-phosphofructo-2-kinasewith an AU-rich instability element: Role intumor cell glycolysis and the Warburg effect. Proc. Natl. Acad. Sci.USA, 1999; 96: 3047-3052
  Google Scholar
• 15. Christofk H.R., Vander-Heiden M.G., Harris M.H., RamanathanA., Gerszten R.E., Wei R., Fleming M.D., Schreiber S.L., Cantley L.C.:The M2 splice isoform of pyruvate kinase is important for cancermetabolism and tumour growth. Nature, 2008; 452: 230-233
  Google Scholar
• 16. Dang C.V.: MYC on the path to cancer. Cell, 2012; 149: 22-35
  Google Scholar
• 17. Dang C.V.: Rethinking the Warburg effect with Myc micromanagingglutamine metabolism. Cancer Res., 2010; 70: 859-862
  Google Scholar
• 18. Darville M.I., Antoine I.V., Rousseau G.G.: Characterization ofan enhancer upstream from the muscle-type promoter of a geneencoding 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase.Nucleic Acids Res., 1992; 20: 3575-3583
  Google Scholar
• 19. DeBerardinis R.J., Lum J.J., Hatzivassiliou G., Thompson C.B.: Thebiology of cancer: metabolic reprogramming fuels cell growth andproliferation. Cell Metab., 2008; 7: 11-20
  Google Scholar
• 20. Dennis P.B., Jaeschke A., Saitoh M., Fowler B., Kozma S.C., ThomasG.: Mammalian TOR: a homeostatic ATP sensor. Science, 2001;294: 1102-1105
  Google Scholar
• 21. Deprez J., Bertrand L., Alessi D.R., Krause U., Hue L., Rider M.H.:Partial purification and characterization of a wortmannin-sensitiveand insulin-stimulated protein kinase that activates heart 6-phosphofructo-2-kinase.Biochem. J., 2000; 347: 305-312
  Google Scholar
• 22. Deprez J., Vertommen D., Alessi D.R., Hue L., Rider M.H.: Phosphorylationand activation of heart 6-phosphofructo-2-kinase byprotein kinase B and other protein kinases of the insulin signalingcascades. J. Biol. Chem., 1997; 272: 17269-17275
  Google Scholar
• 23. Diaz-Ruiz R., Averet N., Araiza D., Pinson B., Uribe-Carvajal S.,Devin A., Rigoulet M.: Mitochondrial oxidative phosphorylation isregulated by fructose 1,6-bisphosphate. A possible role in Crabtreeeffect induction? J. Biol. Chem., 2008; 283: 26948-26955
  Google Scholar
• 24. Diaz-Ruiz R., Rigoulet M., Devin A.: The Warburg and Crabtreeeffects: on the origin of cancer cell energy metabolism and of yeastglucose repression. Biochim. Biophys. Acta, 2011; 1807: 568-576
  Google Scholar
• 25. Du J.Y., Wang L.F., Wang Q., Yu L.D.: miR-26b inhibits proliferation,migration, invasion and apoptosis induction via the downregulationof 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3driven glycolysis in osteosarcoma cells. Oncol. Rep., 2015;33: 1890-1898
  Google Scholar
• 26. Dupriez V.J., Darville M.I., Antoine I.V., Gegonne A., Ghysdael J.,Rousseau G.G.: Characterization of a hepatoma mRNA transcribedfrom a third promoter of a 6-phosphofructo-2-kinase/fructose-2,6–bisphosphatase-encoding gene and controlled by ets oncogene–related products. Proc. Natl. Acad. Sci. USA, 1993; 90: 8224-8228
  Google Scholar
• 27. Fais S., Venturi G., Gatenby B.: Microenvironmental acidosis incarcinogenesis and metastases: New strategies in prevention and therapy. Cancer Metastasis Rev., 2014; 33: 1095-1108
  Google Scholar
• 28. Fernandez-Checa J.C., Kaplowitz N., Garcia-Ruiz C., Colell A.,Miranda M., Mari M., Ardite E., Morales A.: GSH transport in mitochondria:defense against TNF-induced oxidative stress and alcohol–induced defect. Am. J. Physiol., 1997; 273: G7-G17
  Google Scholar
• 29. Fukasawa M., Tsuchiya T., Takayama E., Shinomiya N., UyedaK., Sakakibara R., Seki S.: Identification and characterization of thehypoxia-responsive element of the human placental 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatasegene. J. Biochem., 2004;136: 273-277
  Google Scholar
• 30. Garcia-Cao I., Song M.S., Hobbs R.M., Laurent G., Giorgi C., deBoer V.C., Anastasiou D., Ito K., Sasaki A.T., Rameh L., Carracedo A.,Vander Heiden M.G., Cantley L.C., Pinton P., Haigis M.C., Pandolfi P.P.:Systemic elevation of PTEN induces a tumor-suppressive metabolicstate. Cell, 2012; 149: 49-62
  Google Scholar
• 31. Gatt S., Racker E.: Regulatory mechanisms in carbohydrate metabolism.I. Crabtree effect in reconstructed systems. J. Biol. Chem.,1959; 234: 1015-1023
  Google Scholar
• 32. Ge X., Lyu P., Cao Z., Li J., Guo G., Xia W., Gu Y.: Overexpressionof miR-206 suppresses glycolysis, proliferation and migration inbreast cancer cells via PFKFB3 targeting. Biochem. Biophys. Res.Commun., 2015; 463: 1115-1121
  Google Scholar
• 33. Goidts V., Bageritz J., Puccio L., Nakata S., Zapatka M., BarbusS., Toedt G., Campos B., Korshunov A., Momma S., Van SchaftingenE., Reifenberger G., Herold-Mende C., Lichter P., RadlwimmerB.: RNAi screening in glioma stem-like cells identifies PFKFB4 as akey molecule important for cancer cell survival. Oncogene, 2012;31: 3235-3243
  Google Scholar
• 34. Hanahan D., Weinberg R.A.: Hallmarks of cancer: the next generation.Cell, 2011; 144: 646-674
  Google Scholar
• 35. Herrero-Mendez A., Almeida A., Fernandez E., Maestre C., MoncadaS, Bolanos J.P.: The bioenergetic and antioxidant status of neuronsis controlled by continuous degradation of a key glycolytic enzymeby APC/C-Cdh1. Nat. Cell Biol., 2009; 11: 747-752
  Google Scholar
• 36. Imbert-Fernandez Y., Clem B.F., O’Neal J., Kerr D.A., SpauldingR., Lanceta L., Clem A.L., Telang S., Chesney J.: Estradiol stimulatesglucose metabolism via 6-phosphofructo-2-kinase (PFKFB3). J. Biol.Chem., 2014; 289: 9440-9448
  Google Scholar
• 37. James S.J., Melnyk S., Pogribna M., Pogribny I.P., Caudill M.A.:Elevation in S-adenosylhomocysteine and DNA hypomethylation:Potential epigenetic mechanism for homocysteine-related pathology.J. Nutr., 2002; 132: 2361S-2366S
  Google Scholar
• 38. Jenkins C.M., Yang J., Sims H.F., Gross R.W.: Reversible high affinityinhibition of phosphofructokinase-1 by acyl-CoA: a mechanismintegrating glycolytic flux with lipid metabolism. J. Biol. Chem.,2011; 286: 11937-11950
  Google Scholar
• 39. Kessler R., Eschrich K.: Splice isoforms of ubiquitous 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatasein human brain. BrainRes. Mol. Brain Res., 2001; 87: 190-195
  Google Scholar
• 40. Kim J.W., Gao P., Liu Y.C., Semenza G.L., Dang C.V.: Hypoxia-induciblefactor 1 and dysregulated c-Myc cooperatively induce vascularendothelial growth factor and metabolic switches hexokinase 2 andpyruvate dehydrogenase kinase 1. Mol. Cell Biol., 2007; 27: 7381-7393
  Google Scholar
• 41. Kim J.W., Zeller K.I., Wang Y., Jegga A.G., Aronow B.J., O’DonnellK.A., Dang C.V.: Evaluation of myc E-box phylogenetic footprints inglycolytic genes by chromatin immunoprecipitation assays. Mol.Cell. Biol., 2004; 24: 5923-5936
  Google Scholar
• 42. Koppenol W.H., Bounds P.L., Dang C.V.: Otto Warburg’s contributionsto current concepts of cancer metabolism. Nat. Rev. Cancer,2011; 11: 325-337
  Google Scholar
• 43. Kumar P., Gullberg U., Olsson I., Ajore R.: Myeloid translocationgene-16 co-repressor promotes degradation of hypoxia-induciblefactor 1. PLoS One, 2015; 10: e0123725
  Google Scholar
• 44. Laplante M., Sabatini D.M.: mTOR signaling in growth controland disease. Cell, 2012; 149: 274-293
  Google Scholar
• 45. Li B., Takeda K., Ishikawa K., Yoshizawa M., Sato M., Shibahara S.,Furuyama K.: Coordinated expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 and heme oxygenase 2: Evidence fora regulatory link between glycolysis and heme catabolism. TohokuJ. Exp. Med., 2012; 228: 27-41
  Google Scholar
• 46. Liou G.Y., Storz P.: Reactive oxygen species in cancer. Free Radic.Res., 2010; 44: 479-496
  Google Scholar
• 47. Locasale J.W., Cantley L.C.: Metabolic flux and the regulation ofmammalian cell growth. Cell Metab., 2011; 14: 443-451
  Google Scholar
• 48. Manola J., Atkins M., Ibrahim J., Kirkwood J.: Prognostic factorsin metastatic melanoma: A pooled analysis of Eastern CooperativeOncology Group trials. J. Clin. Oncol., 2000; 18: 3782-3793
  Google Scholar
• 49. Marsin A.S., Bouzin C., Bertrand L., Hue L.: The stimulation ofglycolysis by hypoxia in activated monocytes is mediated by AMPactivatedprotein kinase and inducible 6-phosphofructo-2-kinase.J. Biol. Chem., 2002; 277: 30778-30783
  Google Scholar
• 50. Minchenko A., Leshchinsky I., Opentanova I., Sang N., SrinivasV., Armstead V., Caro J.: Hypoxia-inducible factor-1-mediated expressionof the 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3(PFKFB3) gene. Its possible role in the Warburg effect. J. Biol. Chem.,2002; 277: 6183-6187
  Google Scholar
• 51. Minchenko O., Opentanova I., Caro J.: Hypoxic regulation ofthe 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase genefamily (PFKFB-1-4) expression in vivo. FEBS Lett., 2003; 554: 264-270
  Google Scholar
• 52. Minchenko O., Opentanova I., Minchenko D., Ogura T., EsumiH.: Hypoxia induces transcription of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-4 gene via hypoxia-inducible factor-1αactivation. FEBS Lett., 2004; 576: 14-20
  Google Scholar
• 53. Minchenko O.H., Ogura T., Opentanova I.L., Minchenko D.O.,Ochiai A., Caro J., Komisarenko S.V., Esumi H.: 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase gene family overexpressionin human lung tumor. Ukr. Biokhim. Zh., 2005; 77: 46-50
  Google Scholar
• 54. Minchenko O.H., Opentanova I.L., Ogura T., Minchenko D.O.,Komisarenko S.V., Caro J., Esumi H.: Expression and hypoxia-responsivenessof 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 in mammary gland malignant cell lines. Acta Biochim. Pol., 2005;52: 881-888
  Google Scholar
• 55. Moreno-Sanchez R., Rodriguez-Enriquez S., Marin-HernandezA., Saavedra E.: Energy metabolism in tumor cells. FEBS J., 2007;274: 1393-1418
  Google Scholar
• 56. Navarro-Sabate A., Manzano A., Riera L., Rosa J.L., Ventura F.,Bartrons R.: The human ubiquitous 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatasegene (PFKFB3): Promoter characterizationand genomic structure. Gene., 2001; 264: 131-138
  Google Scholar
• 57. Novellasdemunt L., Bultot L., Manzano A., Ventura F., Rosa J.L.,Vertommen D., Rider M.H., Navarro-Sabate A., Bartrons R.: PFKFB3activation in cancer cells by the p38/MK2 pathway in response tostress stimuli. Biochem. J., 2013; 452: 531-543
  Google Scholar
• 58. Novellasdemunt L., Obach M., Millan-Arino L., Manzano A., VenturaF., Rosa J.L., Jordan A., Navarro-Sabate A., Bartrons R.: Progestinsactivate 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) in breast cancer cells. Biochem. J., 2012; 442: 345-356
  Google Scholar
• 59. Obach M., Navarro-Sabate A., Caro J., Kong X., Duran J., GomezM., Perales J.C., Ventura F., Rosa J.L., Bartrons R.: 6-Phosphofructo-2-kinase (pfkfb3) gene promoter contains hypoxia-inducible factor-1binding sites necessary for transactivation in response to hypoxia.J. Biol. Chem., 2004; 279: 53562-53570
  Google Scholar
• 60. Okar D.A., Lange A.J.: Fructose-2,6-bisphosphate and control ofcarbohydrate metabolism in eukaryotes. Biofactors, 1999; 10: 1-14
  Google Scholar
• 61. Okar D.A., Manzano A., Navarro-Sabate A., Riera L., Bartrons R., Lange A.J.: PFK-2/FBPase-2: Maker and breaker of the essentialbiofactor fructose-2,6-bisphosphate. Trends Biochem. Sci., 2001;26: 30-35
  Google Scholar
• 62. Osthus R.C., Shim H., Kim S., Li Q., Reddy R., Mukherjee M., XuY., Wonsey D., Lee L.A., Dang C.V.: Deregulation of glucose transporter 1 and glycolytic gene expression by c-Myc. J. Biol. Chem.,2000; 275: 21797-21800
  Google Scholar
• 63. Peet A., Lieberman M.A., Marks A.: Marks’ Basic Medical Biochemistry.A Clinical Approach, 2005; p.897
  Google Scholar
• 64. Pilkis S.J., Claus T.H., Kurland I.J., Lange A.J.: 6-Phosphofructo–2-kinase/fructose-2,6-bisphosphatase: A metabolic signaling enzyme.Annu. Rev. Biochem., 1995; 64: 799-835
  Google Scholar
• 65. Pilkis S.J., el-Maghrabi M.R., Claus T.H.: Hormonal regulationof hepatic gluconeogenesis and glycolysis. Annu. Rev. Biochem.,1998; 57: 755-783
  Google Scholar
• 66. Pilkis S.J., Fox E., Wolfe L., Rothbarth L., Colosia A., Stewart H.B.,el-Maghrabi M.R.: Hormonal modulation of key hepatic regulatoryenzymes in the gluconeogenic/glycolytic pathway. Ann. N Y Acad.Sci., 1986; 478: 1-19
  Google Scholar
• 67. Raffaghello L., Lee C., Safdie F.M., Wei M., Madia F., Bianchi G.,Longo V.D.: Starvation-dependent differential stress resistance protectsnormal but not cancer cells against high-dose chemotherapy.Proc. Natl. Acad. Sci. USA, 2008; 105: 8215-8220
  Google Scholar
• 68. Rider M.H., Bertrand L., Vertommen D., Michels P.A., RousseauG.G., Hue L.: 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase:head-to-head with a bifunctional enzyme that controls glycolysis.Biochem. J., 2004; 381: 561-579
  Google Scholar
• 69. Rider M.H., van Damme J., Vertommen D., Michel A., VandekerckhoveJ., Hue L.: Evidence for new phosphorylation sites for proteinkinase C and cyclic AMP-dependent protein kinase in bovine heart6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase. FEBS Lett.,1992; 310: 139-142
  Google Scholar
• 70. Rodriguez-Enriquez S., Juarez O., Rodriguez-Zavala J.S., Moreno-SanchezR.: Multisite control of the Crabtree effect in asciteshepatoma cells. Eur. J. Biochem., 2001; 268: 2512-2519
  Google Scholar
• 71. Ros S., Santos C.R., Moco S., Baenke F., Kelly G., Howell M., ZamboniN., Schulze A.: Functional metabolic screen identifies 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 as an importantregulator of prostate cancer cell survival. Cancer Discov., 2012; 2:328-343
  Google Scholar
• 72. Ros S., Schulze A.: Balancing glycolytic flux: the role of 6-phosphofructo-2-kinase/fructose2,6-bisphosphatases in cancer metabolism.Cancer Metab., 2013; 1: 8
  Google Scholar
• 73. Schafer Z.T., Grassian A.R., Song L., Jiang Z., Gerhart-Hines Z.,Irie H.Y., Gao S., Puigserver P., Brugge J.S.: Antioxidant and oncogenerescue of metabolic defects caused by loss of matrix attachment.Nature, 2009; 461: 109-113
  Google Scholar
• 74. Semenza G.L.: HIF-1 mediates metabolic responses to intratumoralhypoxia and oncogenic mutations. J. Clin. Invest., 2013; 123:3664-3671
  Google Scholar
• 75. Semenza G.L.: Hypoxia-inducible factor 1 (HIF-1) pathway. Sci.STKE, 2007; 407: cm8
  Google Scholar
• 76. Seo M., Lee Y.H.: PFKFB3 regulates oxidative stress homeostasisvia its S-glutathionylation in cancer. J. Mol. Biol., 2014; 426: 830-842
  Google Scholar
• 77. Shim H., Dolde C., Lewis B.C., Wu C.S., Dang G., Jungmann R.A.,Dalla-Favera R., Dang C.V.: c-Myc transactivation of LDH-A: Implicationsfor tumor metabolism and growth. Proc. Natl. Acad. Sci. USA,1997; 94: 6658-6663
  Google Scholar
• 78. Shim H., Lewis B.C., Dolde C., Li Q., Wu C.S., Chun Y.S., Dang C.V.:Myc target genes in neoplastic transformation. Curr. Top. Microbiol.Immunol., 1997; 224: 181-190
  Google Scholar
• 79. Soga T.: Cancer metabolism: Key players in metabolic reprogramming. Cancer Sci., 2013; 104: 275-281
  Google Scholar
• 80. Sola-Penna M., Da Silva D., Coelho W.S., Marinho-Carvalho M.M.,Zancan P.: Regulation of mammalian muscle type 6-phosphofructo-1-kinaseand its implication for the control of the metabolism.IUBMB Life., 2010; 62: 791-796
  Google Scholar
• 81. Song M.S., Carracedo A., Salmena L., Song S.J., Egia A., MalumbresM., Pandolfi P.P.: Nuclear PTEN regulates the APC-CDH1 tumor–suppressive complex in a phosphatase-independent manner. Cell,2011; 144: 187-199
  Google Scholar
• 82. Telang S., Yalcin A., Clem A.L., Bucala R., Lane A.N., Eaton J.W.,Chesney J.: Ras transformation requires metabolic control by 6-phosphofructo-2-kinase.Oncogene, 2006; 25: 7225-7234
  Google Scholar
• 83. Uyeda K., Furuya E., Luby L.J.: The effect of natural and syntheticD-fructose 2,6-bisphosphate on the regulatory kinetic propertiesof liver and muscle phosphofructokinases. J. Biol. Chem., 1981; 256:8394-8399
  Google Scholar
• 84. Van Schaftingen E.: Fructose 2,6-bisphosphate. Adv. Enzymol.Relat. Areas Mol. Biol., 1987; 59: 315-395
  Google Scholar
• 85. Van Schaftingen E., Hue L., Hers H.G.: Fructose 2,6-bisphosphate,the probably structure of the glucose- and glucagon-sensitivestimulator of phosphofructokinase. Biochem. J., 1980; 192: 897-901
  Google Scholar
• 86. Vander Heiden M.G., Cantley L.C., Thompson C.B.: Understandingthe Warburg effect: The metabolic requirements of cell proliferation.Science, 2009; 324: 1029-1033
  Google Scholar
• 87. Vaughn A.E., Deshmukh M.: Glucose metabolism inhibits apoptosisin neurons and cancer cells by redox inactivation of cytochromec. Nat. Cell. Biol., 2008; 10: 1477-1483
  Google Scholar
• 88. Veech R.L., Lawson J.W., Cornell N.W., Krebs H.A.: Cytosolic phosphorylationpotential. J. Biol. Chem., 1979; 254: 6538-6547
  Google Scholar
• 89. Walenta S., Salameh A., Lyng H., Evensen J.F., Mitze M., RofstadE.K., Mueller-Klieser W.: Correlation of high lactate levels in headand neck tumors with incidence of metastasis. Am. J. Pathol., 1997;150: 409-415
  Google Scholar
• 90. Walenta S., Wetterling M., Lehrke M., Schwickert G., Sundfor K.,Rofstad E.K., Mueller-Klieser W.: High lactate levels predict likelihoodof metastases, tumor recurrence, and restricted patient survival inhuman cervical cancers. Cancer Res., 2000; 60: 916-921
  Google Scholar
• 91. Warburg O.: On respiratory impairment in cancer cells. Science,1956; 124: 269-270
  Google Scholar
• 92. Warburg O., Wind F., Negelein E.: The metabolism of tumors inthe body. J. Gen. Physiol., 1927; 8: 519-530
  Google Scholar
• 93. Wu C., Khan S.A., Peng L.J., Lange A.J.: Roles for fructose-2,6-bisphosphate in the control of fuel metabolism: beyond its allostericeffects on glycolytic and gluconeogenic enzymes. Adv. EnzymeRegul., 2006; 46: 72-88
  Google Scholar
• 94. Yalcin A., Clem B.F., Imbert-Fernandez Y., Ozcan S.C., Peker S.,O’Neal J., Klarer A.C., Clem A.L., Telang S., Chesney J.: 6-Phosphofructo-2-kinase(PFKFB3) promotes cell cycle progression and suppressesapoptosis via Cdk1-mediated phosphorylation of p27. CellDeath Dis., 2014; 5: e1337
  Google Scholar
• 95. Yalcin A., Clem B.F., Simmons A., Lane A., Nelson K., Clem A.L.,Brock E., Siow D., Wattenberg B., Telang S., Chesney J.: Nuclear targetingof 6-phosphofructo-2-kinase (PFKFB3) increases proliferationvia cyclin-dependent kinases. J. Biol. Chem., 2009; 284: 24223-24232
  Google Scholar
• 96. Yalcin A., Telang S., Clem B., Chesney J.: Regulation of glucosemetabolism by 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatasesin cancer. Exp. Mol. Pathol., 2009; 86: 174-179
  Google Scholar
• 97. Yamamoto T., Takano N., Ishiwata K., Ohmura M., Nagahata Y.,Matsuura T., Kamata A., Sakamoto K., Nakanishi T., Kubo A., HishikiT., Suematsu M.: Reduced methylation of PFKFB3 in cancer cellsshunts glucose towards the pentose phosphate pathway. Nat. Commun.,2014; 5: 3480
  Google Scholar
• 98. Yecies J.L., Manning B.D.: mTOR links oncogenic signaling totumor cell metabolism. J. Mol. Med., 2011; 89: 221-228
  Google Scholar
• 99. Yecies J.L., Manning B.D.: Transcriptional control of cellularmetabolism by mTOR signaling. Cancer Res., 2011; 71: 2815-2820
  Google Scholar
• 100. Yun S.J., Jo S.W., Ha Y.S., Lee O.J., Kim W.T., Kim Y.J., Lee S.C., KimW.J.: PFKFB4 as a prognostic marker in non-muscle-invasive bladdercancer. Urol. Oncol., 2012; 30: 893-899
  Google Scholar
• 101. Zhang J., Yao Y.H., Li B.G., Yang Q., Zhang P.Y., Wang H.T.: Prognosticvalue of pretreatment serum lactate dehydrogenase level inpatients with solid tumors: A systematic review and meta-analysis.Sci. Rep., 2015; 5: 9800
  Google Scholar
• 102. Zhong H., De Marzo A.M., Laughner E., Lim M., Hilton D.A., ZagzagD., Buechler P., Isaacs W.B., Semenza G.L., Simons J.W.: Overexpressionof hypoxia-inducible factor 1α in common human cancersand their metastases. Cancer Res., 1999; 59: 5830-5835
  Google Scholar
• 103. Zu X.L., Guppy M.: Cancer metabolism: Facts, fantasy, and fiction.Biochem. Biophys. Res. Commun., 2004; 313: 459-465
  Google Scholar

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