Abstract
The genetic basis of increased glycolytic activity observed in cancer cells is likely to be the result of complex interactions of multiple regulatory pathways. Here we review the recent evidence of a simple genetic mechanism by which tumor suppressor p53 regulates mitochondrial respiration with secondary changes in glycolysis that are reminiscent of the Warburg effect. The biological significance of this regulation of the two major pathways of energy generation by p53 remains to be seen.
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Bensaad K, Tsuruta A, Selak MA, Vidal MN, Nakano K, Bartrons R, Gottlieb E, Vousden KH (2006) TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell 126:107–120
Bunz F, Dutriaux A, Lengauer C, Waldman T, Zhou S, Brown JP, Sedivy JM, Kinzler KW, Vogelstein B (1998) Requirement for p53 and p21 to sustain G2 arrest after DNA damage. Science 282:1497–1501
Bustamante E, Pedersen PL (1977) High aerobic glycolysis of rat hepatoma cells in culture: role of mitochondrial hexokinase. Proc Natl Acad Sci USA 74:3735–3739
Elstrom RL, Bauer DE, Buzzai M, Karnauskas R, Harris MH, Plas DR, Zhuang H, Cinalli RM, Alavi A, Rudin CM, Thompson CB (2004) Akt stimulates aerobic glycolysis in cancer cells. Cancer Res 64:3892–3899
Feng Z, Zhang H, Levine AJ, Jin S (2005) The coordinate regulation of the p53 and mTOR pathways in cells. Proc Natl Acad Sci USA 102:8204–8209
Heerdt BG, Halsey HK, Lipkin M, Augenlicht LH (1990) Expression of mitochondrial cytochrome c oxidase in human colonic cell differentiation, transformation, and risk for colonic cancer. Cancer Res 50:1596–1600
Herrmann PC, Gillespie JW, Charboneau L, Bichsel VE, Paweletz CP, Calvert VS, Kohn EC, Emmert-Buck MR, Liotta LA, Petricoin EF III (2003) Mitochondrial proteome: altered cytochrome c oxidase subunit levels in prostate cancer. Proteomics 3:1801–1810
Hofseth LJ, Hussain SP, Harris CC (2004) p53: 25 years after its discovery. Trends Pharmacol Sci 25:177–181
Ibrahim MM, Razmara M, Nguyen D, Donahue RJ, Wubah JA, Knudsen TB (1998) Biochimica et Biophysica Acta (BBA). Mol Cell Res 1403:254–264
Jones RG, Plas DR, Kubek S, Buzzai M, Mu J, Xu Y, Birnbaum MJ, Thompson CB (2005) AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol Cell 18:283–293
Kondoh H, Lleonart ME, Gil J, Wang J, Degan P, Peters G, Martinez D, Carnero A, Beach D (2005) Glycolytic enzymes can modulate cellular life span. Cancer Res 65:177–185
Li F, Wang Y, Zeller KI, Potter JJ, Wonsey DR, O’Donnell KA, Kim JW, Yustein JT, Lee LA, Dang CV (2005) Myc stimulates nuclearly encoded mitochondrial genes and mitochondrial biogenesis. Mol Cell Biol 25:6225–6234
Luciakova K, Kuzela S (1992) Increased steady-state levels of several mitochondrial and nuclear gene transcripts in rat hepatoma with a low content of mitochondria. Eur J Biochem 205:1187–1193
Mathupala SP, Heese C, Pedersen PL (1997) Glucose catabolism in cancer cells. The type II hexokinase promoter contains functionally active response elements for the tumor suppressor p53. J Biol Chem 272:22776–22780
Matoba S, Kang JG, Patino WD, Wragg A, Boehm M, Gavrilova O, Hurley PJ, Bunz F, Hwang PM (2006) p53 regulates mitochondrial respiration. Science 312:1650–1653
Modica-Napolitano JS, Singh KK (2004) Mitochondrial dysfunction in cancer. Mitochondrion 4:755–762
Okamura S, Ng CC, Koyama K, Takei Y, Arakawa H, Monden M, Nakamura Y (1999) Identification of seven genes regulated by wild-type p53 in a colon cancer cell line carrying a well-controlled wild-type p53 expression system. Oncol Res 11:281–285
Olivier M, Eeles R, Hollstein M, Khan MA, Harris CC, Hainaut P (2002) The IARC TP53 database: new online mutation analysis and recommendations to users. Hum Mutat 19:607–614
Polyak K, Li Y, Zhu H, Lengauer C, Willson JK, Markowitz SD, Trush MA, Kinzler KW, Vogelstein B (1998) Somatic mutations of the mitochondrial genome in human colorectal tumours. Nat Genet 20:291–293
Ruiz-Lozano P, Hixon ML, Wagner MW, Flores AI, Ikawa S, Baldwin AS Jr, Chien KR, Gualberto A (1999) p53 is a transcriptional activator of the muscle-specific phosphoglycerate mutase gene and contributes in vivo to the control of its cardiac expression. Cell Growth Differ 10:295–306
Sariban-Sohraby S, Magrath IT, Balaban RS (1983) Comparison of energy metabolism in human normal and neoplastic (Burkitt’s lymphoma) lymphoid cells. Cancer Res 43:4662–4664
Schuhmacher M, Staege MS, Pajic A, Polack A, Weidle UH, Bornkamm GW, Eick D, Kohlhuber F (1999) Control of cell growth by c-Myc in the absence of cell division. Curr Biol 9:1255–1258
Schulz TJ, Thierbach R, Voigt A, Drewes G, Mietzner B, Steinberg P, Pfeiffer AF, Ristow M (2006) Induction of oxidative metabolism by mitochondrial frataxin inhibits cancer growth: Otto Warburg revisited. J Biol Chem 281:977–981
Schwartzenberg-Bar-Yoseph F, Armoni M, Karnieli E (2004) The tumor suppressor p53 down-regulates glucose transporters GLUT1 and GLUT4 gene expression. Cancer Res 64:2627–2633
Vogelstein B, Kinzler KW (2004) Cancer genes and the pathways they control. Nat Med 10:789–799
Warburg O (1956) Science 123:309–314
Zhou S, Kachhap S, Singh KK (2003) Mitochondrial impairment in p53-deficient human cancer cells. Mutagenesis 18:287–292
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Ma, W., Sung, H.J., Park, J.Y. et al. A pivotal role for p53: balancing aerobic respiration and glycolysis. J Bioenerg Biomembr 39, 243–246 (2007). https://doi.org/10.1007/s10863-007-9083-0
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DOI: https://doi.org/10.1007/s10863-007-9083-0