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6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3) is up-regulated in high-grade astrocytomas

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Abstract

The bifunctional enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2/FBPase-2) controls the glycolytic flux via the allosteric activator fructose 2,6-bisphosphate. Because of its proto-oncogenic character, the PFK-2/FBPase-2 of the PFKFB3 gene is assumed to play a critical role in tumorigenesis. We investigated the PFKFB3 expression in 40 human astrocytic gliomas and 20 non-neoplastic brain tissue specimens. The PFKFB3 protein levels were markedly elevated in high-grade astrocytomas relative to low-grade astrocytomas and corresponding non-neoplastic brain tissue, whereas no significant increase of PFKFB3 mRNA was observed in high-grade astrocytomas when compared with control tissue. In the group of glioblastomas the PFKFB3 protein inversely correlates with EGFR expression. The findings demonstrate that PFKFB3 up-regulation is a hallmark of high-grade astrocytomas offering an explanation for high glycolytic flux and lactate production in these tumors.

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References

  1. Maher EA, Furnari FB, Bachoo RM et al (2001) Malignant glioma: genetics biology of a grave matter. Genes Dev 15:1311–1333

    Article  PubMed  CAS  Google Scholar 

  2. Kleihues P, Cavenee WK (2000) World Health Organization classification of tumours of the nervous system. IARC Press, Lyon

    Google Scholar 

  3. Ohgaki H, Kleihues P (2007) Genetic pathways to primary and secondary glioblastoma. Am J Pathol 170:1445–1453

    Article  PubMed  CAS  Google Scholar 

  4. Warburg O (1956) On the origin of cancer cells. Science 123:309–314

    Article  PubMed  CAS  Google Scholar 

  5. Di Chiro G, DeLaPaz RL, Brooks RA et al (1982) Glucose utilization of cerebral gliomas measured by [18F] fluorodeoxyglucose and positron emission tomography. Neurology 32:1323–1329

    PubMed  Google Scholar 

  6. Lohle PN, Wurzer HA, Seelen PJ et al (1998) Analysis of fluid in cysts accompanying various primary and metastatic brain tumours: proteins, lactate and pH. Acta Neurochir 140:14–19

    Article  CAS  Google Scholar 

  7. Howe FA, Barton SJ, Cudlip SA et al (2003) Metabolic profiles of human brain tumors using quantitative in vivo 1H magnetic resonance spectroscopy. Magn Reson Med 49:223–232

    Article  PubMed  CAS  Google Scholar 

  8. Boado RJ, Black KL, Pardridge WM (1994) Gene expression of GLUT3 and GLUT1 glucose transporters in human brain tumors. Brain Res Mol Brain Res 27:51–57

    Article  PubMed  CAS  Google Scholar 

  9. Oudard S, Arvelo F, Miccoli L et al (1996) High glycolysis in gliomas despite low hexokinase transcription and activity correlated to chromosome 10 loss. Br J Cancer 74:839–845

    PubMed  CAS  Google Scholar 

  10. Meixensberger J, Herting B, Roggendorf W et al (1995) Metabolic patterns in malignant gliomas. J Neurooncol 24:153–161

    Article  PubMed  CAS  Google Scholar 

  11. Oudard S, Boitier E, Miccoli L et al (1997) Gliomas are driven by glycolysis: putative roles of hexokinase, oxidative phosphorylation and mitochondrial ultrastructure. Anticancer Res 17:1903–1911

    PubMed  CAS  Google Scholar 

  12. Van Schaftingen E, Jett MF, Hue L, Hers HG (1981) Control of liver 6-phosphofructokinase by fructose 2,6-bisphosphate and other effectors. Proc Natl Acad Sci USA 78:3483–3486

    Article  PubMed  Google Scholar 

  13. Okar DA, Manzano A, Navarro-Sabate A et al (2001) PFK-2/FBPase-2: maker and breaker of the essential biofactor fructose-2,6-bisphosphate. Trends Biochem Sci 26:30–35

    Article  PubMed  CAS  Google Scholar 

  14. Rider MH, Bertrand L, Vertommen D et al (2004) 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase: head-to-head with a bifunctional enzyme that controls glycolysis. Biochem J 381:561–579

    Article  PubMed  CAS  Google Scholar 

  15. El-Maghrabi MR, Noto F, Wu N et al (2001) 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase: suiting structure to need, in a family of tissue-specific enzymes. Curr Opin Clin Nutr Metab Care 4:411–418

    Article  PubMed  CAS  Google Scholar 

  16. Chesney J, Mitchell R, Benigni F et al (1999) An inducible gene product for 6-phosphofructo-2-kinase with an AU-rich instability element: role in tumor cell glycolysis and the Warburg effect. Proc Natl Acad Sci USA 16:3047–3052

    Article  Google Scholar 

  17. Manzano A, Rosa JL, Ventura F et al (1998) Molecular cloning, expression, and chromosomal localization of a ubiquitously expressed human 6-phosphofructo-2-kinase/ fructose-2, 6-bisphosphatase gene (PFKFB3). Cytogenet Cell Genet 83:214–217

    Article  PubMed  CAS  Google Scholar 

  18. Kessler R, Eschrich K (2001) Splice isoforms of ubiquitous 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase in human brain. Brain Res Mol Brain Res 87:190–195

    Article  PubMed  CAS  Google Scholar 

  19. Chen CY, Shyu AB (1995) AU-rich elements: characterization and importance in mRNA degradation. Trends Biochem Sci 20:465–470

    Article  PubMed  CAS  Google Scholar 

  20. Chesney J (2006) 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase and tumor cell glycolysis. Curr Opin Clin Nutr Metab Care 9:535–539

    Article  PubMed  CAS  Google Scholar 

  21. Calvo MN, Bartrons R, Castano E et al (2006) PFKFB3 gene silencing decreases glycolysis, induces cell-cycle delay and inhibits anchorage-independent growth in HeLa cells. FEBS Lett 580:3308–3314

    Article  PubMed  CAS  Google Scholar 

  22. Telang S, Yalcin A, Clem AL et al (2006) Ras transformation requires metabolic control by 6-phosphofructo-2-kinase. Oncogene 25:7225–7234

    Article  PubMed  CAS  Google Scholar 

  23. Hamilton JA, Callaghan MJ, Sutherland RL et al (1997) Identification of PRG1, a novel progestin-responsive gene with sequence homology to 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase. Mol Endocrinol 11:490–502

    Article  PubMed  CAS  Google Scholar 

  24. Hirata T, Kato M, Okamura N et al (1998) Expression of human placental-type 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase in various cells and cell lines. Biochem Biophys Res Commun 242:680–684

    Article  PubMed  CAS  Google Scholar 

  25. Atsumi T, Chesney J, Metz C et al (2002) High expression of inducible 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (iPFK-2; PFKFB3) in human cancers. Cancer Res 62:5881–5887

    PubMed  CAS  Google Scholar 

  26. Minchenko OH, Ochiai A, Opentanova IL et al (2005) Overexpression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-4 in the human breast and colon malignant tumors. Biochimie 87:1005–1010

    Article  PubMed  CAS  Google Scholar 

  27. Nabors LB, Gillespie GY, Harkins L et al (2001) HuR, a RNA stability factor, is expressed in malignant brain tumors and binds to adenine-and uridine-rich elements within the 3′ untranslated regions of cytokine and angiogenic factor mRNAs. Cancer Res 61:2154–2161

    PubMed  CAS  Google Scholar 

  28. Ohgaki H (2005) Genetic pathways to glioblastomas. Neuropathology 25:1–7

    Article  PubMed  Google Scholar 

  29. Fujisawa H, Reis RM, Nakamura M et al (2000) Loss of heterozygosity on chromosome 10 is more extensive in primary (de novo) than in secondary glioblastomas. Lab Invest 80:65–72

    Article  PubMed  CAS  Google Scholar 

  30. Wong AJ, Bigner SH, Bigner DD et al (1987) Increased expression of the epidermal growth factor receptor gene in malignant gliomas is invariably associated with gene amplification. Proc Natl Acad Sci USA 84:6899–6903

    Article  PubMed  CAS  Google Scholar 

  31. Schlegel J, Merdes A, Stumm G et al (1994) Amplification of the epidermal-growth-factor-receptor gene correlates with different growth behaviour in human glioblastoma. Int J Cancer 56:72–77

    Article  PubMed  CAS  Google Scholar 

  32. Minchenko A, Leshchinsky I, Opentanova I et al (2002) Hypoxia-inducible factor-1-mediated expression of the 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) gene. Its possible role in the Warburg effect. J Biol Chem 277:6183–6187

    Article  PubMed  CAS  Google Scholar 

  33. Sakakibara R, Kato M, Okamura N et al (1997) Characterization of a human placental fructose-6-phosphate 2-kinase/fructose-2,6-bisphosphatase. J Biochem 122:122–128

    PubMed  CAS  Google Scholar 

  34. Zagzag D, Zhong H, Scalzitti JM et al (2000) Expression of hypoxia-inducible factor 1alpha in brain tumors: association with angiogenesis, invasion, and progression. Cancer 88:2606–2618

    Article  PubMed  CAS  Google Scholar 

  35. Zhong H, De Marzo AM, Laughner E et al (1999) Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases. Cancer Res 59:5830–5835

    PubMed  CAS  Google Scholar 

  36. Dixon DA, Balch GC, Kedersha N et al (2003) Regulation of cyclooxygenase-2 expression by the translational silencer TIA-1. J Exp Med 198:475–481

    Article  PubMed  CAS  Google Scholar 

  37. Lal A, Kawai T, Yang X et al (2005) Antiapoptotic function of RNA-binding protein HuR effected through prothymosin alpha. EMBO J 24:1852–1862

    Article  PubMed  CAS  Google Scholar 

  38. Kita D, Yonekawa Y, Weller M, Ohgaki H (2007) PIK3CA alterations in primary (de novo) and secondary glioblastomas. Acta Neuropathol 113:295–302

    Article  PubMed  CAS  Google Scholar 

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Acknowledgement

This work was supported by the Wilhelm-Sander-Stiftung (2004.010.1).

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Correspondence to Klaus Eschrich.

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Kessler, R., Bleichert, F., Warnke, JP. et al. 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3) is up-regulated in high-grade astrocytomas. J Neurooncol 86, 257–264 (2008). https://doi.org/10.1007/s11060-007-9471-7

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  • DOI: https://doi.org/10.1007/s11060-007-9471-7

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