Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

How do glycolytic enzymes favour cancer cell proliferation by nonmetabolic functions?

Oncogene volume 34, pages 3751–3759 (2015)Cite this article

Subjects

Abstract

Cancer cells enhance their glycolysis, producing lactate, even in the presence of oxygen. Glycolysis is a series of ten metabolic reactions catalysed by enzymes whose expression is most often increased in tumour cells. HKII and phosphoglucose isomerase (PGI) have mainly an antiapoptotic effect; PGI and glyceraldehyde-3-phosphate dehydrogenase activate survival pathways (Akt and so on); phosphofructokinase 1 and triose phosphate isomerase participate in cell cycle activation; aldolase promotes epithelial mesenchymal transition; PKM2 enhances various nuclear effects such as transcription, stabilisation and so on. This review outlines the multiple non-glycolytic roles of glycolytic enzymes, which are essential for promoting cancer cells' survival, proliferation, chemoresistance and dissemination.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Hinkle PC . P/O ratios of mitochondrial oxidative phosphorylation. Biochim Biophys Acta 2005; 1706: 1–11.

    CAS  PubMed  Google Scholar 

  2. Deberardinis RJ, Cheng T . Q's next: the diverse functions of glutamine in metabolism, cell biology and cancer. Oncogene 2010; 29: 313–324.

    CAS  PubMed  Google Scholar 

  3. Porporato PE, Dhup S, Dadhich RK, Copetti T, Sonveaux P . Anticancer targets in the glycolytic metabolism of tumors: a comprehensive review. Front Pharmacol 2011; 2: 49.

    PubMed  PubMed Central  Google Scholar 

  4. Nieman KM, Kenny HA, Penicka CV, Ladanyi A, Buell-Gutbrod R, Zillhardt MR et al. Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nat Med 2011; 17: 1498–1503.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Icard P, Lincet H . A global view of the biochemical pathways involved in the regulation of the metabolism of cancer cells. Biochim Biophys Acta 2012; 1826: 423–433.

    CAS  PubMed  Google Scholar 

  6. Cairns RA, Harris IS, Mak TW . Regulation of cancer cell metabolism. Nat Rev Cancer 2011; 11: 85–95.

    CAS  PubMed  Google Scholar 

  7. Semenza GL . Regulation of metabolism by hypoxia-inducible factor 1. Cold Spring Harb Symp Quant Biol 2011; 76: 347–353.

    CAS  PubMed  Google Scholar 

  8. Hanahan D, Weinberg RA . Hallmarks of cancer: the next generation. Cell 2011; 144: 646–674.

    CAS  PubMed  Google Scholar 

  9. Locasale JW, Grassian AR, Melman T, Lyssiotis CA, Mattaini KR, Bass AJ et al. Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis. Nat Genet 2011; 31: 869–874.

    Google Scholar 

  10. Posemato R, Marks KM, Shaul YD, Pacold ME, Kim D, Birsoy K et al. Functional genomics reveal that the serine synthesis pathway is essential in breast cancer. Nature 2011; 476: 346–350.

    Google Scholar 

  11. Chen JQ, Russo J . Dysregulation of glucose transport, glycolysis, TCA cycle and glutaminolysis by oncogenes and tumor suppressors in cancer cells. Biochim Biophys Acta 2012; 1826: 370–384.

    CAS  PubMed  Google Scholar 

  12. Jang M, Kim SS, Lee J . Cancer cell metabolism: implications for therapeutic targets. Exp Mol Med 2013; 45: e45.

    PubMed  PubMed Central  Google Scholar 

  13. Kroemer G, Pouyssegur J . Tumor cell metabolism: cancer's Achilles' heel. Cancer Cell 2008; 13: 472–482.

    CAS  PubMed  Google Scholar 

  14. Shinohara Y, Yamamoto K, Kogure K, Ichihara J, Terada H . Steady state transcript levels of the type II hexokinase and type 1 glucose transporter in human tumor cell lines. Cancer Lett 1994; 82: 27–32.

    CAS  PubMed  Google Scholar 

  15. Pedersen PL, Mathupala S, Rempel A, Geschwind JF, Ko YH . Mitochondrial bound type II hexokinase: a key player in the growth and survival of many cancers and an ideal prospect for therapeutic intervention. Biochim Biophys Acta 2002; 1555: 14–20.

    CAS  PubMed  Google Scholar 

  16. Wilson JE . Isozymes of mammalian hexokinase: structure, subcellular localization and metabolic function. J Exp Biol 2003; 206: 2049–2057.

    CAS  PubMed  Google Scholar 

  17. Patra KC, Wang Q, Bhaskar PT, Miller L, Wang Z, Wheaton W et al. Hexokinase 2 is required for tumor initiation and maintenance and its systemic deletion is therapeutic in mouse models of cancer. Cancer Cell 2013; 24: 213–228.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Mathupala SP, Ko YH, Pedersen PL . The pivotal roles of mitochondria in cancer: Warburg and beyond and encouraging prospects for effective therapies. Biochim Biophys Acta 2010; 1797: 1225–1230.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Bustamante E, Pedersen PL . High aerobic glycolysis of rat hepatoma cells in culture: role of mitochondrial hexokinase. Proc Natl Acad Sci USA 1977; 74: 3735–3739.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Gottlob K, Majewski N, Kennedy S, Kandel E, Robey RB, Hay N . Inhibition of early apoptotic events by Akt/PKB is dependent on the first committed step of glycolysis and mitochondrial hexokinase. Genes Dev 2001; 15: 1406–1418.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Ravagnan L, Roumier T, Kroemer G . Mitochondria, the killer organelles and their weapons. J Cell Physiol 2002; 192: 131–137.

    CAS  PubMed  Google Scholar 

  22. Majewski N, Nogueira V, Bhaskar P, Coy PE, Skeen JE, Gottlob K et al. Hexokinase-mitochondria interaction mediated by Akt is required to inhibit apoptosis in the presence or absence of Bax and Bak. Mol Cell 2004; 16: 819–830.

    CAS  PubMed  Google Scholar 

  23. Pastorino JG, Hoek JB . Hexokinase II: the integration of energy metabolism and control of apoptosis. Curr Med Chem 2003; 10: 1535–1551.

    CAS  PubMed  Google Scholar 

  24. Danial NN, Gramm CF, Scorrano L, Zhang CY, Krauss S, Ranger AM et al. BAD and glucokinase reside in a mitochondrial complex that integrates glycolysis and apoptosis. Nature 2003; 424: 952–956.

    CAS  PubMed  Google Scholar 

  25. Yang J, Li JH, Wang J, Zhang CY . Molecular modeling of BAD complex resided in a mitochondrion integrating glycolysis and apoptosis. J Theor Biol 2010; 266: 231–241.

    CAS  PubMed  Google Scholar 

  26. Min JW, Kim KI, Kim HA, Kim EK, Noh WC, Jeon HB et al. INPP4B-mediated tumor resistance is associated with modulation of glucose metabolism via hexokinase 2 regulation in laryngeal cancer cells. Biochem Biophys Res Commun 2013; 440: 137–142.

    CAS  PubMed  Google Scholar 

  27. Palmieri D, Fitzgerald D, Shreeve SM, Hua E, Bronder JL, Weil RJ et al. Analyses of resected human brain metastases of breast cancer reveal the association between up-regulation of hexokinase 2 and poor prognosis. Mol Cancer Res 2009; 7: 1438–1445.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Kwee SA, Hernandez B, Chan O, Wong L . Choline kinase alpha and hexokinase-2 protein expression in hepatocellular carcinoma: association with survival. PLoS ONE 2012; 7: e46591.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Chen J, Zhang S, Li Y, Tang Z, Kong W . Hexokinase 2 overexpression promotes the proliferation and survival of laryngeal squamous cell carcinoma. Tumour Biol 2014; 35: 3743–3753.

    CAS  PubMed  Google Scholar 

  30. Kim JW, Gao P, Liu YC, Semenza GL, Dang CV . Hypoxia-inducible factor 1 and dysregulated c-Myc cooperatively induce vascular endothelial growth factor and metabolic switches hexokinase 2 and pyruvate dehydrogenase kinase 1. Mol Cell Biol 2007; 27: 7381–7393.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Yeung SJ, Pan J, Lee MH . Roles of p53, MYC and HIF-1 in regulating glycolysis - the seventh hallmark of cancer. Cell Mol Life Sci 2008; 65: 3981–3999.

    CAS  PubMed  Google Scholar 

  32. Peschiaroli A, Giacobbe A, Formosa A, Markert EK, Bongiorno-Borbone L, Levine AJ et al. miR-143 regulates hexokinase 2 expression in cancer cells. Oncogene 2013; 32: 797–802.

    CAS  PubMed  Google Scholar 

  33. Jiang S, Zhang LF, Zhang HW, Hu S, Lu MH, Liang S et al. A novel miR-155/miR-143 cascade controls glycolysis by regulating hexokinase 2 in breast cancer cells. EMBO J 2012; 31: 1985–1998.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Jiang S, Zhang HW, Lu MH, He XH, Li Y, Gu H et al. MicroRNA-155 functions as an OncomiR in breast cancer by targeting the suppressor of cytokine signaling 1 gene. Cancer Res 2010; 70: 3119–3127.

    CAS  PubMed  Google Scholar 

  35. Watanabe H, Takehana K, Date M, Shinozaki T, Raz A . Tumor cell autocrine motility factor is the neuroleukin/phosphohexose isomerase polypeptide. Cancer Res 1996; 56: 2960–2963.

    CAS  PubMed  Google Scholar 

  36. Liotta LA, Mandler R, Murano G, Katz DA, Gordon RK, Chiang PK et al. Tumor cell autocrine motility factor. Proc Natl Acad Sci USA 1986; 83: 3302–3306.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Baumann M, Kappl A, Lang T, Brand K, Siegfried W, Paterok E . The diagnostic validity of the serum tumor marker phosphohexose isomerase (PHI) in patients with gastrointestinal, kidney, and breast cancer. Cancer Invest 1990; 8: 351–356.

    CAS  PubMed  Google Scholar 

  38. Tsutsumi S, Hogan V, Nabi IR, Raz A . Overexpression of the autocrine motility factor/phosphoglucose isomerase induces transformation and survival of NIH-3T3 fibroblasts. Cancer Res 2003; 63: 242–249.

    CAS  PubMed  Google Scholar 

  39. Niinaka Y, Paku S, Haga A, Watanabe H, Raz A . Expression and secretion of neuroleukin/phosphohexose isomerase/maturation factor as autocrine motility factor by tumor cells. Cancer Res 1998; 58: 2667–2674.

    CAS  PubMed  Google Scholar 

  40. Nabi IR, Watanabe H, Raz A . Autocrine motility factor and its receptor: role in cell locomotion and metastasis. Cancer Metastasis Rev 1992; 11: 5–20.

    CAS  PubMed  Google Scholar 

  41. Funasaka T, Yanagawa T, Hogan V, Raz A . Regulation of phosphoglucose isomerase/autocrine motility factor expression by hypoxia. FASEB J 2005; 19: 1422–1430.

    CAS  PubMed  Google Scholar 

  42. Araki K, Shimura T, Yajima T, Tsutsumi S, Suzuki H, Okada K et al. Phosphoglucose isomerase/autocrine motility factor promotes melanoma cell migration through ERK activation dependent on autocrine production of interleukin-8. J Biol Chem 2009; 284: 32305–32311.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Haga A, Funasaka T, Niinaka Y, Raz A, Nagase H . Autocrine motility factor signaling induces tumor apoptotic resistance by regulations Apaf-1 and Caspase-9 apoptosome expression. Int J Cancer 2003; 107: 707–714.

    CAS  PubMed  Google Scholar 

  44. Kho DH, Nangia-Makker P, Balan V, Hogan V, Tait L, Wang Y et al. Autocrine motility factor promotes HER2 cleavage and signaling in breast cancer cells. Cancer Res 2013; 73: 1411–1419.

    CAS  PubMed  Google Scholar 

  45. Fruman DA, Rommel C . PI3K and cancer: lessons, challenges and opportunities. Nat Rev Drug Discov 2014; 13: 140–156.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. You ZM, Zhao L, Xia J, Wei Q, Liu YM, Liu XY et al. Down-regulation of phosphoglucose isomerase/autocrine motility factor enhances gensenoside Rh2 pharmacological action on leukemia KG1alpha cells. Asian Pac J Cancer Prev 2014; 15: 1099–1104.

    PubMed  Google Scholar 

  47. Niinaka Y, Harada K, Fujimuro M, Oda M, Haga A, Hosoki M et al. Silencing of autocrine motility factor induces mesenchymal-to-epithelial transition and suppression of osteosarcoma pulmonary metastasis. Cancer Res 2010; 70: 9483–9493.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Thiery JP, Acloque H, Huang RY, Nieto MA . Epithelial-mesenchymal transitions in development and disease. Cell 2009; 139: 871–890.

    CAS  PubMed  Google Scholar 

  49. Vendrell JA, Thollet A, Nguyen NT, Ghayad SE, Vinot S, Bieche I et al. ZNF217 is a marker of poor prognosis in breast cancer that drives epithelial-mesenchymal transition and invasion. Cancer Res 2012; 72: 3593–3606.

    CAS  PubMed  Google Scholar 

  50. Ahmad A, Aboukameel A, Kong D, Wang Z, Sethi S, Chen W et al. Phosphoglucose isomerase/autocrine motility factor mediates epithelial-mesenchymal transition regulated by miR-200 in breast cancer cells. Cancer Res 2011; 71: 3400–3409.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Jenkins CM, Yang J, Sims HF, Gross RW . Reversible high affinity inhibition of phosphofructokinase-1 by acyl-CoA: a mechanism integrating glycolytic flux with lipid metabolism. J Biol Chem 2011; 286: 11937–11950.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Costa LT, Da SD, Guimaraes CR, Zancan P, Sola-Penna M . Lactate favours the dissociation of skeletal muscle 6-phosphofructo-1-kinase tetramers down-regulating the enzyme and muscle glycolysis. Biochem J 2007; 408: 123–130.

    Google Scholar 

  53. Ros S, Schulze A . Balancing glycolytic flux: the role of 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatases in cancer metabolism. Cancer Metab 2013; 1: 8.

    PubMed  PubMed Central  Google Scholar 

  54. Yi W, Clark PM, Mason DE, Keenan MC, Hill C, Goddard WA III et al. Phosphofructokinase 1 glycosylation regulates cell growth and metabolism. Science 2012; 337: 975–980.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Van SE, Hue L, Hers HG . Fructose 2,6-bisphosphate, the probably structure of the glucose- and glucagon-sensitive stimulator of phosphofructokinase. Biochem J 1980; 192: 897–901.

    Google Scholar 

  56. Rider MH, Bertrand L, Vertommen D, Michels PA, Rousseau GG, 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.

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  58. Chesney J . 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase and tumor cell glycolysis. Curr Opin Clin Nutr Metab Care 2006; 9: 535–539.

    CAS  PubMed  Google Scholar 

  59. Yalcin A, Clem BF, Simmons A, Lane A, Nelson K, Clem AL et al. Nuclear targeting of 6-phosphofructo-2-kinase (PFKFB3) increases proliferation via cyclin-dependent kinases. J Biol Chem 2009; 284: 24223–24232.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Almeida A, Bolanos JP, Moncada S . E3 ubiquitin ligase APC/C-Cdh1 accounts for the Warburg effect by linking glycolysis to cell proliferation. Proc Natl Acad Sci USA 2010; 107: 738–741.

    CAS  PubMed  Google Scholar 

  61. Mukai T, Joh K, Arai Y, Yatsuki H, Hori K . Tissue-specific expression of rat aldolase A mRNAs. Three molecular species differing only in the 5'-terminal sequences. J Biol Chem 1986; 261: 3347–3354.

    CAS  PubMed  Google Scholar 

  62. Asaka M, Kimura T, Meguro T, Kato M, Kudo M, Miyazaki T et al. Alteration of aldolase isozymes in serum and tissues of patients with cancer and other diseases. J Clin Lab Anal 1994; 8: 144–148.

    CAS  PubMed  Google Scholar 

  63. Du S, Guan Z, Hao L, Song Y, Wang L, Gong L et al. Fructose-bisphosphate aldolase a is a potential metastasis-associated marker of lung squamous cell carcinoma and promotes lung cell tumorigenesis and migration. PLoS ONE 2014; 9: e85804.

    PubMed  PubMed Central  Google Scholar 

  64. Poschmann G, Sitek B, Sipos B, Ulrich A, Wiese S, Stephan C et al. Identification of proteomic differences between squamous cell carcinoma of the lung and bronchial epithelium. Mol Cell Proteomics 2009; 8: 1105–1116.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Chaerkady R, Harsha HC, Nalli A, Gucek M, Vivekanandan P, Akhtar J et al. A quantitative proteomic approach for identification of potential biomarkers in hepatocellular carcinoma. J Proteome Res 2008; 7: 4289–4298.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Kim JH, Lee S, Kim JH, Lee TG, Hirata M, Suh PG et al. Phospholipase D2 directly interacts with aldolase via Its PH domain. Biochemistry 2002; 41: 3414–3421.

    CAS  PubMed  Google Scholar 

  67. Kao AW, Noda Y, Johnson JH, Pessin JE, Saltiel AR . Aldolase mediates the association of F-actin with the insulin-responsive glucose transporter GLUT4. J Biol Chem 1999; 274: 17742–17747.

    CAS  PubMed  Google Scholar 

  68. Buscaglia CA, Penesetti D, Tao M, Nussenzweig V . Characterization of an aldolase-binding site in the Wiskott-Aldrich syndrome protein. J Biol Chem 2006; 281: 1324–1331.

    CAS  PubMed  Google Scholar 

  69. Ritterson LC, Tolan DR . Targeting of several glycolytic enzymes using RNA interference reveals aldolase affects cancer cell proliferation through a non-glycolytic mechanism. J Biol Chem 2012; 287: 42554–42563.

    Google Scholar 

  70. Saez DE, Slebe JC . Subcellular localization of aldolase B. J Cell Biochem 2000; 78: 62–72.

    CAS  PubMed  Google Scholar 

  71. Satou W, Tanimoto H, Ukekawa R, Fujii M, Ayusawa D . Amplification of nuclear aldolase A in mouse cell mutants resistant to Hoechst 33342. Biochem Biophys Res Commun 2004; 315: 845–849.

    CAS  PubMed  Google Scholar 

  72. Gao ZH, Metherall J, Virshup DM . Identification of casein kinase I substrates by in vitro expression cloning screening. Biochem Biophys Res Commun 2000; 268: 562–566.

    CAS  PubMed  Google Scholar 

  73. Laplante M, Sabatini DM . Regulation of mTORC1 and its impact on gene expression at a glance. J Cell Sci 2013; 126: 1713–1719.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Mamczur P, Gamian A, Kolodziej J, Dziegiel P, Rakus D . Nuclear localization of aldolase A correlates with cell proliferation. Biochim Biophys Acta 2013; 1833: 2812–2822.

    CAS  PubMed  Google Scholar 

  75. Ronai Z, Robinson R, Rutberg S, Lazarus P, Sardana M . Aldolase-DNA interactions in a SEWA cell system. Biochim Biophys Acta 1992; 1130: 20–28.

    CAS  PubMed  Google Scholar 

  76. Canete-Soler R, Reddy KS, Tolan DR, Zhai J . Aldolases a and C are ribonucleolytic components of a neuronal complex that regulates the stability of the light-neurofilament mRNA. J Neurosci 2005; 25: 4353–4364.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Lu J, Suzuki T, Satoh M, Chen S, Tomonaga T, Nomura F et al. Involvement of aldolase A in X-ray resistance of human HeLa and UV(r)-1 cells. Biochem Biophys Res Commun 2008; 369: 948–952.

    CAS  PubMed  Google Scholar 

  78. Wierenga RK, Kapetaniou EG, Venkatesan R . Triosephosphate isomerase: a highly evolved biocatalyst. Cell Mol Life Sci 2010; 67: 3961–3982.

    CAS  PubMed  Google Scholar 

  79. Chen G, Gharib TG, Huang CC, Thomas DG, Shedden KA, Taylor JM et al. Proteomic analysis of lung adenocarcinoma: identification of a highly expressed set of proteins in tumors. Clin Cancer Res 2002; 8: 2298–2305.

    CAS  PubMed  Google Scholar 

  80. Li C, Xiao Z, Chen Z, Zhang X, Li J, Wu X et al. Proteome analysis of human lung squamous carcinoma. Proteomics 2006; 6: 547–558.

    CAS  PubMed  Google Scholar 

  81. Unwin RD, Craven RA, Harnden P, Hanrahan S, Totty N, Knowles M et al. Proteomic changes in renal cancer and co-ordinate demonstration of both the glycolytic and mitochondrial aspects of the Warburg effect. Proteomics 2003; 3: 1620–1632.

    CAS  PubMed  Google Scholar 

  82. Di MM, Marcone S, Cicchillitti L, Della CA, Ferlini C, Scambia G et al. Glycoproteomics of paclitaxel resistance in human epithelial ovarian cancer cell lines: towards the identification of putative biomarkers. J Proteomics 2010; 73: 879–898.

    Google Scholar 

  83. Gruning NM, Du D, Keller MA, Luisi BF, Ralser M . Inhibition of triosephosphate isomerase by phosphoenolpyruvate in the feedback-regulation of glycolysis. Open Biol 2014; 4: 130232.

    PubMed  PubMed Central  Google Scholar 

  84. Ying W . NAD+/NADH and NADP+/NADPH in cellular functions and cell death: regulation and biological consequences. Antioxid Redox Signal 2008; 10: 179–206.

    CAS  PubMed  Google Scholar 

  85. Kruger A, Gruning NM, Wamelink MM, Kerick M, Kirpy A, Parkhomchuk D et al. The pentose phosphate pathway is a metabolic redox sensor and regulates transcription during the antioxidant response. Antioxid Redox Signal 2011; 15: 311–324.

    PubMed  Google Scholar 

  86. Gruning NM, Rinnerthaler M, Bluemlein K, Mulleder M, Wamelink MM, Lehrach H et al. Pyruvate kinase triggers a metabolic feedback loop that controls redox metabolism in respiring cells. Cell Metab 2011; 14: 415–427.

    PubMed  PubMed Central  Google Scholar 

  87. Lee WH, Choi JS, Byun MR, Koo KT, Shin S, Lee SK et al. Functional inactivation of triosephosphate isomerase through phosphorylation during etoposide-induced apoptosis in HeLa cells: potential role of Cdk2. Toxicology 2010; 278: 224–228.

    CAS  PubMed  Google Scholar 

  88. Wang X, Lu Y, Yang J, Shi Y, Lan M, Liu Z et al. Identification of triosephosphate isomerase as an anti-drug resistance agent in human gastric cancer cells using functional proteomic analysis. J Cancer Res Clin Oncol 2008; 134: 995–1003.

    CAS  PubMed  Google Scholar 

  89. Guo C, Liu S, Sun MZ . Novel insight into the role of GAPDH playing in tumor. Clin Transl Oncol 2013; 15: 167–172.

    CAS  PubMed  Google Scholar 

  90. Demarse NA, Ponnusamy S, Spicer EK, Apohan E, Baatz JE, Ogretmen B et al. Direct binding of glyceraldehyde 3-phosphate dehydrogenase to telomeric DNA protects telomeres against chemotherapy-induced rapid degradation. J Mol Biol 2009; 394: 789–803.

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Colell A, Green DR, Ricci JE . Novel roles for GAPDH in cell death and carcinogenesis. Cell Death Differ 2009; 16: 1573–1581.

    CAS  PubMed  Google Scholar 

  92. Hara MR, Agrawal N, Kim SF, Cascio MB, Fujimuro M, Ozeki Y et al. S-nitrosylated GAPDH initiates apoptotic cell death by nuclear translocation following Siah1 binding. Nat Cell Biol 2005; 7: 665–674.

    CAS  PubMed  Google Scholar 

  93. Huang J, Hao L, Xiong N, Cao X, Liang Z, Sun S et al. Involvement of glyceraldehyde-3-phosphate dehydrogenase in rotenone-induced cell apoptosis: relevance to protein misfolding and aggregation. Brain Res 2009; 1279: 1–8.

    CAS  PubMed  Google Scholar 

  94. Tarze A, Deniaud A, Le BM, Maillier E, Molle D, Larochette N et al. GAPDH, a novel regulator of the pro-apoptotic mitochondrial membrane permeabilization. Oncogene 2007; 26: 2606–2620.

    CAS  PubMed  Google Scholar 

  95. Krynetski EY, Krynetskaia NF, Bianchi ME, Evans WE . A nuclear protein complex containing high mobility group proteins B1 and B2, heat shock cognate protein 70, ERp60, and glyceraldehyde-3-phosphate dehydrogenase is involved in the cytotoxic response to DNA modified by incorporation of anticancer nucleoside analogues. Cancer Res 2003; 63: 100–106.

    CAS  PubMed  Google Scholar 

  96. Meyer-Siegler K, Rahman-Mansur N, Wurzer JC, Sirover MA . Proliferative dependent regulation of the glyceraldehyde-3-phosphate dehydrogenase/uracil DNA glycosylase gene in human cells. Carcinogenesis 1992; 13: 2127–2132.

    CAS  PubMed  Google Scholar 

  97. Chang CH, Curtis JD, Maggi LB Jr, Faubert B, Villarino AV, O'Sullivan D et al. Posttranscriptional control of T cell effector function by aerobic glycolysis. Cell 2013; 153: 1239–1251.

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Tristan C, Shahani N, Sedlak TW, Sawa A . The diverse functions of GAPDH: views from different subcellular compartments. Cell Signal 2011; 23: 317–323.

    CAS  PubMed  Google Scholar 

  99. Nicholls C, Pinto AR, Li H, Li L, Wang L, Simpson R et al. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) induces cancer cell senescence by interacting with telomerase RNA component. Proc Natl Acad Sci USA 2012; 109: 13308–13313.

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Krasnov GS, Dmitriev AA, Snezhkina AV, Kudryavtseva AV . Deregulation of glycolysis in cancer: glyceraldehyde-3-phosphate dehydrogenase as a therapeutic target. Expert Opin Ther Targets 2013; 17: 681–693.

    CAS  PubMed  Google Scholar 

  101. Sirover MA . Subcellular dynamics of multifunctional protein regulation: mechanisms of GAPDH intracellular translocation. J Cell Biochem 2012; 113: 2193–2200.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Huang W, Wang Z, Lei QY . Acetylation control of metabolic enzymes in cancer: an updated version. Acta Biochim Biophys Sin (Shanghai) 2014; 46: 204–213.

    CAS  Google Scholar 

  103. Joo HY, Woo SR, Shen YN, Yun MY, Shin HJ, Park ER et al. SIRT1 interacts with and protects glyceraldehyde-3-phosphate dehydrogenase (GAPDH) from nuclear translocation: implications for cell survival after irradiation. Biochem Biophys Res Commun 2012; 424: 681–686.

    CAS  PubMed  Google Scholar 

  104. Li T, Liu M, Feng X, Wang Z, Das I, Xu Y et al. Glyceraldehyde-3-phosphate dehydrogenase is activated by lysine 254 acetylation in response to glucose signal. J Biol Chem 2014; 289: 3775–3785.

    CAS  PubMed  Google Scholar 

  105. Sen N, Hara MR, Kornberg MD, Cascio MB, Bae BI, Shahani N et al. Nitric oxide-induced nuclear GAPDH activates p300/CBP and mediates apoptosis. Nat Cell Biol 2008; 10: 866–873.

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Ventura M, Mateo F, Serratosa J, Salaet I, Carujo S, Bachs O et al. Nuclear translocation of glyceraldehyde-3-phosphate dehydrogenase is regulated by acetylation. Int J Biochem Cell Biol 2010; 42: 1672–1680.

    CAS  PubMed  Google Scholar 

  107. Huang Q, Lan F, Zheng Z, Xie F, Han J, Dong L et al. Akt2 kinase suppresses glyceraldehyde-3-phosphate dehydrogenase (GAPDH)-mediated apoptosis in ovarian cancer cells via phosphorylating GAPDH at threonine 237 and decreasing its nuclear translocation. J Biol Chem 2011; 286: 42211–42220.

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Carujo S, Estanyol JM, Ejarque A, Agell N, Bachs O, Pujol MJ . Glyceraldehyde 3-phosphate dehydrogenase is a SET-binding protein and regulates cyclin B-cdk1 activity. Oncogene 2006; 25: 4033–4042.

    CAS  PubMed  Google Scholar 

  109. Inoki K, Li Y, Xu T, Guan KL . Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev 2003; 17: 1829–1834.

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Colell A, Ricci JE, Tait S, Milasta S, Maurer U, Bouchier-Hayes L et al. GAPDH and autophagy preserve survival after apoptotic cytochrome c release in the absence of caspase activation. Cell 2007; 129: 983–997.

    CAS  PubMed  Google Scholar 

  111. Ren F, Wu H, Lei Y, Zhang H, Liu R, Zhao Y et al. Quantitative proteomics identification of phosphoglycerate mutase 1 as a novel therapeutic target in hepatocellular carcinoma. Mol Cancer 2010; 9: 81–89.

    PubMed  PubMed Central  Google Scholar 

  112. Shen J, Wang W, Wu J, Feng B, Chen W, Wang M et al. Comparative proteomic profiling of human bile reveals SSP411 as a novel biomarker of cholangiocarcinoma. PLoS ONE 2012; 7: e47476.

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Evans MJ, Saghatelian A, Sorensen EJ, Cravatt BF . Target discovery in small-molecule cell-based screens by in situ proteome reactivity profiling. Nat Biotechnol 2005; 23: 1303–1307.

    CAS  PubMed  Google Scholar 

  114. Hamaguchi T, Iizuka N, Tsunedomi R, Hamamoto Y, Miyamoto T, Iida M et al. Glycolysis module activated by hypoxia-inducible factor 1alpha is related to the aggressive phenotype of hepatocellular carcinoma. Int J Oncol 2008; 33: 725–731.

    CAS  PubMed  Google Scholar 

  115. Takahashi Y, Takahashi S, Yoshimi T, Miura T . Hypoxia-induced expression of phosphoglycerate mutase B in fibroblasts. Eur J Biochem 1998; 254: 497–504.

    CAS  PubMed  Google Scholar 

  116. Sharma NK, Sethy NK, Bhargava K . Comparative proteome analysis reveals differential regulation of glycolytic and antioxidant enzymes in cortex and hippocampus exposed to short-term hypobaric hypoxia. J Proteomics 2013; 79: 277–298.

    CAS  PubMed  Google Scholar 

  117. Evans MJ, Morris GM, Wu J, Olson AJ, Sorensen EJ, Cravatt BF . Mechanistic and structural requirements for active site labeling of phosphoglycerate mutase by spiroepoxides. Mol Biosyst 2007; 3: 495–506.

    CAS  PubMed  Google Scholar 

  118. Hitosugi T, Zhou L, Elf S, Fan J, Kang HB, Seo JH et al. Phosphoglycerate mutase 1 coordinates glycolysis and biosynthesis to promote tumor growth. Cancer Cell 2012; 22: 585–600.

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Zhao S, Xu W, Jiang W, Yu W, Lin Y, Zhang T et al. Regulation of cellular metabolism by protein lysine acetylation. Science 2010; 327: 1000–1004.

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Hallows WC, Yu W, Denu JM . Regulation of glycolytic enzyme phosphoglycerate mutase-1 by Sirt1 protein-mediated deacetylation. J Biol Chem 2012; 287: 3850–3858.

    CAS  PubMed  Google Scholar 

  121. Hitosugi T, Zhou L, Fan J, Elf S, Zhang L, Xie J et al. Tyr26 phosphorylation of PGAM1 provides a metabolic advantage to tumours by stabilizing the active conformation. Nat Commun 2013; 4: 1790.

    PubMed  Google Scholar 

  122. Grisolia S, Cleland WW . Influence of salt, substrate, and cofactor concentrations on the kinetic and mechanistic behavior of phosphoglycerate mutase. Biochemistry 1968; 7: 1115–1121.

    CAS  PubMed  Google Scholar 

  123. Vander Heiden MG, Locasale JW, Swanson KD, Sharfi H, Heffron GJ, Amador-Noguez D et al. Evidence for an alternative glycolytic pathway in rapidly proliferating cells. Science 2010; 329: 1492–1499.

    CAS  PubMed  Google Scholar 

  124. Stryer L . Biochemistry. 2nd edition. W. H. Freeman and Company: New York, 1981.

  125. Noguchi T, Inoue H, Tanaka T . The M1- and M2-type isozymes of rat pyruvate kinase are produced from the same gene by alternative RNA splicing. J Biol Chem 1986; 261: 13807–13812.

    CAS  PubMed  Google Scholar 

  126. Noguchi T, Yamada K, Inoue H, Matsuda T, Tanaka T . The L- and R-type isozymes of rat pyruvate kinase are produced from a single gene by use of different promoters. J Biol Chem 1987; 262: 14366–14371.

    CAS  PubMed  Google Scholar 

  127. Mazurek S . Pyruvate kinase type M2: a key regulator of the metabolic budget system in tumor cells. Int J Biochem Cell Biol 2011; 43: 969–980.

    CAS  PubMed  Google Scholar 

  128. Christofk HR, Vander Heiden MG, Harris MH, Ramanathan A, Gerszten RE, Wei R et al. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature 2008; 452: 230–233.

    CAS  PubMed  Google Scholar 

  129. David CJ, Chen M, Assanah M, Canoll P, Manley JL . HnRNP proteins controlled by c-Myc deregulate pyruvate kinase mRNA splicing in cancer. Nature 2010; 463: 364–368.

    CAS  PubMed  Google Scholar 

  130. Chen M, Zhang J, Manley JL . Turning on a fuel switch of cancer: hnRNP proteins regulate alternative splicing of pyruvate kinase mRNA. Cancer Res 2010; 70: 8977–8980.

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Liu J, Wu N, Ma L, Liu M, Liu G, Zhang Y et al. Oleanolic Acid suppresses aerobic glycolysis in cancer cells by switching pyruvate kinase type m isoforms. PLoS ONE 2014; 9: e91606.

    PubMed  PubMed Central  Google Scholar 

  132. Wong N, Ojo D, Yan J, Tang D . PKM2 contributes to cancer metabolism. Cancer Lett 2014(in press).

  133. Desai S, Ding M, Wang B, Lu Z, Zhao Q, Shaw K et al. Tissue-specific isoform switch and DNA hypomethylation of the pyruvate kinase PKM gene in human cancers. Oncotarget 2013; 7: 1–9.

    Google Scholar 

  134. Li J, Yang Z, Zou Q, Yuan Y, Li J, Liang L et al. PKM2 and ACVR 1C are prognostic markers for poor prognosis of gallbladder cancer. Clin Transl Oncol 2014; 16: 200–207.

    PubMed  Google Scholar 

  135. Mukherjee J, Phillips JJ, Zheng S, Wiencke J, Ronen SM, Pieper RO . Pyruvate kinase M2 expression, but not pyruvate kinase activity, is up-regulated in a grade-specific manner in human glioma. PLoS ONE 2013; 8: e57610.

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Zhang X, He C, He C, Chen B, Liu Y, Kong M et al. Nuclear PKM2 expression predicts poor prognosis in patients with esophageal squamous cell carcinoma. Pathol Res Pract 2013; 209: 510–515.

    CAS  PubMed  Google Scholar 

  137. Luo W, Semenza GL . Emerging roles of PKM2 in cell metabolism and cancer progression. Trends Endocrinol Metab 2012; 23: 560–566.

    PubMed  PubMed Central  Google Scholar 

  138. Dhup S, Dadhich RK, Porporato PE, Sonveaux P . Multiple biological activities of lactic Acid in cancer: influences on tumor growth, angiogenesis and metastasis. Curr Pharm Des 2012; 18: 1319–1330.

    CAS  PubMed  Google Scholar 

  139. Chaneton B, Hillmann P, Zheng L, Martin AC, Maddocks OD, Chokkathukalam A et al. Serine is a natural ligand and allosteric activator of pyruvate kinase M2. Nature 2012; 491: 458–462.

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Israelsen WJ, Dayton TL, Davidson SM, Fiske BP, Hosios AM, Bellinger G et al. PKM2 isoform-specific deletion reveals a differential requirement for pyruvate kinase in tumor cells. Cell 2013; 155: 397–409.

    CAS  PubMed  Google Scholar 

  141. Hitosugi T, Kang S, Vander Heiden MG, Chung TW, Elf S, Lythgoe K et al. Tyrosine phosphorylation inhibits PKM2 to promote the Warburg effect and tumor growth. Sci Signal 2009; 2: ra73.

    PubMed  PubMed Central  Google Scholar 

  142. Christofk HR, Vander Heiden MG, Wu N, Asara JM, Cantley LC . Pyruvate kinase M2 is a phosphotyrosine-binding protein. Nature 2008; 452: 181–186.

    CAS  PubMed  Google Scholar 

  143. Iqbal MA, Gupta V, Gopinath P, Mazurek S, Bamezai RN . Pyruvate kinase M2 and cancer: an updated assessment. FEBS Lett 2014; 588: 2685–2692.

    CAS  PubMed  Google Scholar 

  144. Gao X, Wang H, Yang JJ, Liu X, Liu ZR . Pyruvate kinase M2 regulates gene transcription by acting as a protein kinase. Mol Cell 2012; 45: 598–609.

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Lv L, Li D, Zhao D, Lin R, Chu Y, Zhang H et al. Acetylation targets the M2 isoform of pyruvate kinase for degradation through chaperone-mediated autophagy and promotes tumor growth. Mol Cell 2011; 42: 719–730.

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Lv L, Xu YP, Zhao D, Li FL, Wang W, Sasaki N et al. Mitogenic and oncogenic stimulation of K433 acetylation promotes PKM2 protein kinase activity and nuclear localization. Mol Cell 2013; 52: 340–352.

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Yang W, Lu Z . Regulation and function of pyruvate kinase M2 in cancer. Cancer Lett 2013; 339: 153–158.

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Miller DM, Thomas SD, Islam A, Muench D, Sedoris K . c-Myc and cancer metabolism. Clin Cancer Res 2012; 18: 5546–5553.

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Mehla K, Singh PK . MUC1: A novel metabolic master regulator. Biochim Biophys Acta 2014; 1845: 126–135.

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Lau SK, Weiss LM, Chu PG . Differential expression of MUC1, MUC2, and MUC5AC in carcinomas of various sites: an immunohistochemical study. Am J Clin Pathol 2004; 122: 61–69.

    PubMed  Google Scholar 

  151. Kufe DW . Mucins in cancer: function, prognosis and therapy. Nat Rev Cancer 2009; 9: 874–885.

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Nath S, Mukherjee P . MUC1: a multifaceted oncoprotein with a key role in cancer progression. Trends Mol Med 2014; 20: 332–342.

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Kosugi M, Ahmad R, Alam M, Uchida Y, Kufe D . MUC1-C oncoprotein regulates glycolysis and pyruvate kinase M2 activity in cancer cells. PLoS ONE 2011; 6: e28234.

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Stetak A, Veress R, Ovadi J, Csermely P, Keri G, Ullrich A . Nuclear translocation of the tumor marker pyruvate kinase M2 induces programmed cell death. Cancer Res 2007; 67: 1602–1608.

    CAS  PubMed  Google Scholar 

  155. Hoshino A, Hirst JA, Fujii H . Regulation of cell proliferation by interleukin-3-induced nuclear translocation of pyruvate kinase. J Biol Chem 2007; 282: 17706–17711.

    CAS  PubMed  Google Scholar 

  156. Yang W, Zheng Y, Xia Y, Ji H, Chen X, Guo F et al. ERK1/2-dependent phosphorylation and nuclear translocation of PKM2 promotes the Warburg effect. Nat Cell Biol 2012; 14: 1295–1304.

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Wang HJ, Hsieh YJ, Cheng WC, Lin CP, Lin YS, Yang SF et al. JMJD5 regulates PKM2 nuclear translocation and reprograms HIF-1alpha-mediated glucose metabolism. Proc Natl Acad Sci USA 2014; 111: 279–284.

    CAS  PubMed  Google Scholar 

  158. Lee J, Kim HK, Han YM, Kim J . Pyruvate kinase isozyme type M2 (PKM2) interacts and cooperates with Oct-4 in regulating transcription. Int J Biochem Cell Biol 2008; 40: 1043–1054.

    CAS  PubMed  Google Scholar 

  159. Yang W, Xia Y, Ji H, Zheng Y, Liang J, Huang W et al. Nuclear PKM2 regulates beta-catenin transactivation upon EGFR activation. Nature 2011; 480: 118–122.

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Demaria M, Giorgi C, Lebiedzinska M, Esposito G, D'Angeli L, Bartoli A et al. A STAT3-mediated metabolic switch is involved in tumour transformation and STAT3 addiction. Aging (Albany NY) 2010; 2: 823–842.

    CAS  Google Scholar 

  161. Demaria M, Poli V . PKM2, STAT3 and HIF-1alpha: The Warburg's vicious circle. JAKSTAT 2012; 1: 194–196.

    PubMed  PubMed Central  Google Scholar 

  162. Yang P, Li Z, Fu R, Wu H, Li Z . Pyruvate kinase M2 facilitates colon cancer cell migration via the modulation of STAT3 signalling. Cell Signal 2014; 26: 1853–1862.

    CAS  PubMed  Google Scholar 

  163. Wang LY, Liu YP, Chen LG, Chen YL, Tan L, Liu JJ et al. Pyruvate kinase M2 plays a dual role on regulation of the EGF/EGFR signaling via E-cadherin-dependent manner in gastric cancer cells. PLoS ONE 2013; 8: e67542.

    CAS  PubMed  PubMed Central  Google Scholar 

  164. Bauvois B . New facets of matrix metalloproteinases MMP-2 and MMP-9 as cell surface transducers: outside-in signaling and relationship to tumor progression. Biochim Biophys Acta 2012; 1825: 29–36.

    CAS  PubMed  Google Scholar 

  165. Yang W, Xia Y, Hawke D, Li X, Liang J, Xing D et al. PKM2 phosphorylates histone H3 and promotes gene transcription and tumorigenesis. Cell 2012; 150: 685–696.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Locally Aggressive Cancer Biology and Therapy Unit (BioTICLA), Caen, France

    H Lincet & P Icard

  2. Normandie University, Caen, France

    H Lincet

  3. François-Baclesse Centre for Cancer, Caen, France

    H Lincet

  4. Ecole Polytechnique, Laboratoire d’Informatique, Palaiseau, France

    P Icard

Authors
  1. H Lincet
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. P Icard
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to H Lincet.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lincet, H., Icard, P. How do glycolytic enzymes favour cancer cell proliferation by nonmetabolic functions?. Oncogene 34, 3751–3759 (2015). https://doi.org/10.1038/onc.2014.320

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2014.320

This article is cited by

Search

Advanced search

Quick links