Dysregulation of glucose transport, glycolysis, TCA cycle and glutaminolysis by oncogenes and tumor suppressors in cancer cells.

A common set of functional characteristics of cancer cells is that cancer cells consume a large amount of glucose, maintain high rate of glycolysis and convert a majority of glucose into lactic acid even in the presence of oxygen compared to that of normal cells (Warburg's Effects). In addition, cancer cells exhibit substantial alterations in several energy metabolism pathways including glucose transport, tricarboxylic acid (TCA) cycle, glutaminolysis, mitochondrial respiratory chain oxidative phosphorylation and pentose phosphate pathway (PPP). In the present work, we focused on reviewing the current knowledge about the dysregulation of the proteins/enzymes involved in the key regulatory steps of glucose transport, glycolysis, TCA cycle and glutaminolysis by several oncogenes including c-Myc and hypoxia inducible factor-1 (HIF-1) and tumor suppressor, p53, in cancer cells. The dysregulation of glucose transport and energy metabolism pathways by oncogenes and lost functions of the tumor suppressors have been implicated as important biomarkers for cancer detection and as valuable targets for the development of new anticancer therapies.

[1]  R. Airley,et al.  Glut-1 as a therapeutic target: increased chemoresistance and HIF-1-independent link with cell turnover is revealed through COMPARE analysis and metabolomic studies , 2008, Cancer Chemotherapy and Pharmacology.

[2]  R. Bucala,et al.  An inducible gene product for 6-phosphofructo-2-kinase with an AU-rich instability element: role in tumor cell glycolysis and the Warburg effect. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[3]  P. Rustin,et al.  Functional consequences of a SDHB gene mutation in an apparently sporadic pheochromocytoma. , 2002, The Journal of clinical endocrinology and metabolism.

[4]  G. G. Stokes "J." , 1890, The New Yale Book of Quotations.

[5]  K. Chien,et al.  p 53 Is a Transcriptional Activator of the Muscle-specific Phosphoglycerate Mutase Gene and Contributes in Vivo to the Control of Its Cardiac Expression 1 , 2000 .

[6]  A. Levine,et al.  The Control of the Metabolic Switch in Cancers by Oncogenes and Tumor Suppressor Genes , 2010, Science.

[7]  J. Matés,et al.  Expression of functional human glutaminase in baculovirus system: affinity purification, kinetic and molecular characterization. , 2007, The international journal of biochemistry & cell biology.

[8]  Ken Garber,et al.  Energy Deregulation: Licensing Tumors to Grow , 2006, Science.

[9]  Eyal Gottlieb,et al.  Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. , 2005, Cancer cell.

[10]  E. Murphy,et al.  Phosphorylation of Glycogen Synthase Kinase-3&bgr; During Preconditioning Through a Phosphatidylinositol-3-Kinase–Dependent Pathway Is Cardioprotective , 2002, Circulation research.

[11]  C. Stout,et al.  Crystal structures of aconitase with isocitrate and nitroisocitrate bound. , 1993, Biochemistry.

[12]  X. Estivill,et al.  Molecular cloning, expression, and chromosomal localization of a ubiquitously expressed human 6-phosphofructo-2-kinase/ fructose-2,6-bisphosphatase gene (PFKFB3) , 1999, Cytogenetic and Genome Research.

[13]  S. Moncada,et al.  Molecular basis for the differential use of glucose and glutamine in cell proliferation as revealed by synchronized HeLa cells , 2011, Proceedings of the National Academy of Sciences.

[14]  H. Christofk,et al.  Pyruvate kinase M2 is a phosphotyrosine-binding protein , 2008, Nature.

[15]  J. Rathmell,et al.  Cytokine stimulation promotes glucose uptake via phosphatidylinositol-3 kinase/Akt regulation of Glut1 activity and trafficking. , 2007, Molecular biology of the cell.

[16]  L. Liau,et al.  Cancer-associated IDH1 mutations produce 2-hydroxyglutarate , 2009, Nature.

[17]  A. Lange,et al.  Fructose‐2,6‐bisphosphate and control of carbohydrate metabolism in eukaryotes , 1999, BioFactors.

[18]  G L Rosner,et al.  Patterns and variability of tumor oxygenation in human soft tissue sarcomas, cervical carcinomas, and lymph node metastases. , 1995, International journal of radiation oncology, biology, physics.

[19]  P. Rustin,et al.  Tricarboxylic acid cycle dysfunction as a cause of human diseases and tumor formation. , 2006, American journal of physiology. Cell physiology.

[20]  Ming You,et al.  TSC2 Integrates Wnt and Energy Signals via a Coordinated Phosphorylation by AMPK and GSK3 to Regulate Cell Growth , 2006, Cell.

[21]  H. Tonami,et al.  Correlation of Glut-1 glucose transporter expression with. , 2000, European journal of nuclear medicine.

[22]  Taro Higuchi,et al.  Reduced expression and loss of heterozygosity of the SDHD gene in colorectal and gastric cancer. , 2003, Oncology reports.

[23]  G. Semenza,et al.  Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1. , 1994, The Journal of biological chemistry.

[24]  P. Hruz,et al.  Structural analysis of the GLUT1 facilitative glucose transporter (review). , 2001, Molecular membrane biology.

[25]  L. Korotchkina,et al.  Probing the Mechanism of Inactivation of Human Pyruvate Dehydrogenase by Phosphorylation of Three Sites* , 2001, The Journal of Biological Chemistry.

[26]  M. Hendrix,et al.  Role for glucose transporter 1 protein in human breast cancer , 2008, Pathology & Oncology Research.

[27]  R. Deberardinis,et al.  Beyond aerobic glycolysis: Transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis , 2007, Proceedings of the National Academy of Sciences.

[28]  Chris Sander,et al.  18F-fluorodeoxy-glucose positron emission tomography marks MYC-overexpressing human basal-like breast cancers. , 2011, Cancer research.

[29]  J E Bailey,et al.  Glucose catabolism of Escherichia coli strains with increased activity and altered regulation of key glycolytic enzymes. , 1999, Metabolic engineering.

[30]  K. Uyeda,et al.  Regulation of Energy Metabolism in Macrophages during Hypoxia , 2001, The Journal of Biological Chemistry.

[31]  M. Cascante,et al.  Cells overexpressing fructose‐2,6‐bisphosphatase showed enhanced pentose phosphate pathway flux and resistance to oxidative stress , 2000, FEBS letters.

[32]  Tsung-Cheng Chang,et al.  c-Myc suppression of miR-23 enhances mitochondrial glutaminase and glutamine metabolism , 2009, Nature.

[33]  Posttranslational Modification of 6-Phosphofructo-1-Kinase in Aspergillus niger , 2005, Applied and Environmental Microbiology.

[34]  D. Busam,et al.  An Integrated Genomic Analysis of Human Glioblastoma Multiforme , 2008, Science.

[35]  R. Deberardinis,et al.  The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. , 2008, Cell metabolism.

[36]  F. Brosius,et al.  GLUT1 enhances mTOR activity independently of TSC2 and AMPK. , 2011, American journal of physiology. Renal physiology.

[37]  J. Holik,et al.  Akt substrate TBC1D1 regulates GLUT1 expression through the mTOR pathway in 3T3-L1 adipocytes. , 2008, The Biochemical journal.

[38]  N. Sonenberg,et al.  Opposite Translational Control of GLUT1 and GLUT4 Glucose Transporter mRNAs in Response to Insulin , 1999, The Journal of Biological Chemistry.

[39]  C. Harris,et al.  p53 negatively regulates transcription of the pyruvate dehydrogenase kinase Pdk2. , 2012, Cancer research.

[40]  A. Levine,et al.  Glutaminase 2, a novel p53 target gene regulating energy metabolism and antioxidant function , 2010, Proceedings of the National Academy of Sciences.

[41]  G. Semenza,et al.  HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. , 2006, Cell metabolism.

[42]  Anthony Mancuso,et al.  Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction , 2008, Proceedings of the National Academy of Sciences.

[43]  J. Matés,et al.  Genomic organization and transcriptional analysis of the human l-glutaminase gene. , 2003, The Biochemical journal.

[44]  T. Asano,et al.  C-terminal truncated glucose transporter is locked into an inward-facing form without transport activity , 1990, Nature.

[45]  Keshav K. Singh,et al.  Mitochondrial aconitase and citrate metabolism in malignant and nonmalignant human prostate tissues , 2006, Molecular Cancer.

[46]  Richard A. Roth,et al.  Regulation of GLUT1 Gene Transcription by the Serine/Threonine Kinase Akt1* , 1999, The Journal of Biological Chemistry.

[47]  C. Dang,et al.  MYC-Induced Cancer Cell Energy Metabolism and Therapeutic Opportunities , 2009, Clinical Cancer Research.

[48]  K. Erguler,et al.  Citrate enhances in vitro metastatic behaviours of PC-3M human prostate cancer cells: status of endogenous citrate and dependence on aconitase and fatty acid synthase. , 2006, The international journal of biochemistry & cell biology.

[49]  R. McLendon,et al.  IDH1 and IDH2 mutations in gliomas. , 2009, The New England journal of medicine.

[50]  N. Sang,et al.  Hypoxia-inducible Factor-1-mediated Expression of the 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) Gene , 2002, The Journal of Biological Chemistry.

[51]  R. Smith,et al.  Glutamine metabolism and its physiologic importance. , 1990, JPEN. Journal of parenteral and enteral nutrition.

[52]  R. Curi,et al.  Molecular mechanisms of glutamine action , 2005, Journal of cellular physiology.

[53]  Xin Lu,et al.  Metabolomic Changes Accompanying Transformation and Acquisition of Metastatic Potential in a Syngeneic Mouse Mammary Tumor Model* , 2010, The Journal of Biological Chemistry.

[54]  N. Sonenberg,et al.  Upstream and downstream of mTOR. , 2004, Genes & development.

[55]  Nishant Singh,et al.  Dominant Negative Mutations Affect Oligomerization of Human Pyruvate Kinase M2 Isozyme and Promote Cellular Growth and Polyploidy* , 2010, The Journal of Biological Chemistry.

[56]  M. Hayashi,et al.  Induction of glucose transporter 1 expression through hypoxia-inducible factor 1alpha under hypoxic conditions in trophoblast-derived cells. , 2004, The Journal of endocrinology.

[57]  N. Neamati,et al.  A proteomic approach links decreased pyruvate kinase M2 expression to oxaliplatin resistance in patients with colorectal cancer and in human cell lines , 2009, Molecular Cancer Therapeutics.

[58]  R. Sakakibara,et al.  Cloning of cDNA encoding for a novel isozyme of fructose 6-phosphate, 2-kinase/fructose 2,6-bisphosphatase from human placenta. , 1996, Journal of biochemistry.

[59]  C. A. Thomas,et al.  Molecular cloning. , 1977, Advances in pathobiology.

[60]  J. Yates,et al.  Adaptation of energy metabolism in breast cancer brain metastases. , 2007, Cancer research.

[61]  A. Cassago,et al.  Mitochondrial localization and structure-based phosphate activation mechanism of Glutaminase C with implications for cancer metabolism , 2012, Proceedings of the National Academy of Sciences.

[62]  C. Tokunaga,et al.  mTOR integrates amino acid- and energy-sensing pathways. , 2004, Biochemical and biophysical research communications.

[63]  K. M. Popov,et al.  Molecular cloning of the p45 subunit of pyruvate dehydrogenase kinase. , 1994, The Journal of biological chemistry.

[64]  C. Dang Oncogenic alterations of metabolism , 2014 .

[65]  S. Paik,et al.  Clinicopathologic significance of GLUT1 expression and its correlation with Apaf-1 in colorectal adenocarcinomas. , 2011, World journal of gastroenterology.

[66]  Adam D. Richardson,et al.  Central carbon metabolism in the progression of mammary carcinoma , 2007, Breast Cancer Research and Treatment.

[67]  N. Hay,et al.  Akt Inhibits Apoptosis Downstream of BID Cleavage via a Glucose-Dependent Mechanism Involving Mitochondrial Hexokinases , 2004, Molecular and Cellular Biology.

[68]  H. Fujii,et al.  Expression of L- and M-type pyruvate kinase in human tissues. , 1988, Genomics.

[69]  P. Ward,et al.  Metabolic reprogramming: a cancer hallmark even warburg did not anticipate. , 2012, Cancer cell.

[70]  E. Holme,et al.  IDH2 Mutations in Patients with d-2-Hydroxyglutaric Aciduria , 2010, Science.

[71]  B. Glaser,et al.  Germline fumarate hydratase mutations in families with multiple cutaneous and uterine leiomyomata. , 2003, The Journal of investigative dermatology.

[72]  J. Lovén,et al.  Targeting MYC-Regulated miRNAs to Combat Cancer. , 2010, Genes & cancer.

[73]  Yukiko Nakamura,et al.  Biologic correlation of 2-[18F]-fluoro-2-deoxy-D-glucose uptake on positron emission tomography in thymic epithelial tumors. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[74]  J. L. Rosa,et al.  Overexpression of fructose 2,6-bisphosphatase decreases glycolysis and delays cell cycle progression. , 2000, American journal of physiology. Cell physiology.

[75]  Saroj P. Mathupala,et al.  Hexokinase-2 bound to mitochondria: cancer's stygian link to the "Warburg Effect" and a pivotal target for effective therapy. , 2009, Seminars in cancer biology.

[76]  Jörg Marienhagen,et al.  GLUT1 expression is increased in hepatocellular carcinoma and promotes tumorigenesis. , 2009, The American journal of pathology.

[77]  M. Legiša,et al.  Changes in primary metabolism leading to citric acid overflow in Aspergillus niger , 2007, Biotechnology Letters.

[78]  K. Kinzler,et al.  p21 is necessary for the p53-mediated G1 arrest in human cancer cells. , 1995, Cancer research.

[79]  G. Owen,et al.  Glucose transporters: expression, regulation and cancer. , 2002, Biological research.

[80]  J. Fan,et al.  Glucose Transporter-1 as a New Therapeutic Target in Laryngeal Carcinoma , 2010, The Journal of international medical research.

[81]  C. Thompson,et al.  Glutamine addiction: a new therapeutic target in cancer. , 2010, Trends in biochemical sciences.

[82]  L. Leng,et al.  High expression of inducible 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (iPFK-2; PFKFB3) in human cancers. , 2002, Cancer research.

[83]  Christian M. Metallo,et al.  Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia , 2011, Nature.

[84]  David G. Watson,et al.  Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. , 2005, Cancer cell.

[85]  Omar Abdel-Wahab,et al.  The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. , 2010, Cancer cell.

[86]  C. Thompson,et al.  Hexokinase-mitochondria interaction mediated by Akt is required to inhibit apoptosis in the presence or absence of Bax and Bak. , 2004, Molecular cell.

[87]  A. Harris,et al.  Pyruvate dehydrogenase and pyruvate dehydrogenase kinase expression in non small cell lung cancer and tumor-associated stroma. , 2005, Neoplasia.

[88]  Ru Wei,et al.  The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth , 2008, Nature.

[89]  J. Erickson,et al.  Glutaminase: A Hot Spot For Regulation Of Cancer Cell Metabolism? , 2010, Oncotarget.

[90]  Russell G. Jones,et al.  Tumor suppressors and cell metabolism: a recipe for cancer growth. , 2009, Genes & development.

[91]  P. Hruz,et al.  Cysteine-scanning Mutagenesis of Transmembrane Segment 7 of the GLUT1 Glucose Transporter* , 1999, The Journal of Biological Chemistry.

[92]  Oksana Gavrilova,et al.  p53 Regulates Mitochondrial Respiration , 2006, Science.

[93]  Shile Huang,et al.  Curcumin inhibits the mammalian target of rapamycin‐mediated signaling pathways in cancer cells , 2006, International journal of cancer.

[94]  Jun Li,et al.  Distinct structural mechanisms for inhibition of pyruvate dehydrogenase kinase isoforms by AZD7545, dichloroacetate, and radicicol. , 2007, Structure.

[95]  K. Tsui,et al.  p53 downregulates the gene expression of mitochondrial aconitase in human prostate carcinoma cells , 2011, The Prostate.

[96]  Shih-Chieh Lin,et al.  Overexpression of pyruvate dehydrogenase kinase 3 increases drug resistance and early recurrence in colon cancer. , 2011, The American journal of pathology.

[97]  J. Hauf,et al.  Simultaneous genomic overexpression of seven glycolytic enzymes in the yeast Saccharomyces cerevisiae. , 2000, Enzyme and microbial technology.

[98]  G. Staal,et al.  Isoenzymes of phosphofructokinase in the rat. Demonstration of the three non-identical subunits by biochemical, immunochemical and kinetic studies. , 1985, The Biochemical journal.

[99]  M. Legiša,et al.  Highly active, citrate inhibition resistant form of Aspergillus niger 6-phosphofructo-1-kinase encoded by a modified pfkA gene. , 2009, Journal of biotechnology.

[100]  C. Livi,et al.  Reduced Expression of Fumarate Hydratase in Clear Cell Renal Cancer Mediates HIF-2α Accumulation and Promotes Migration and Invasion , 2011, PloS one.

[101]  Saroj P. Mathupala,et al.  Glucose Catabolism in Cancer Cells , 2001, The Journal of Biological Chemistry.

[102]  P. Chumakov,et al.  The antioxidant function of the p53 tumor suppressor , 2005, Nature Medicine.

[103]  William R Sellers,et al.  TSC2 regulates VEGF through mTOR-dependent and -independent pathways. , 2003, Cancer cell.

[104]  L. Porter,et al.  QLS motif in transmembrane helix VII of the glucose transporter family interacts with the C-1 position of D-glucose and is involved in substrate selection at the exofacial binding site. , 1998, Biochemistry.

[105]  H. Brunengraber,et al.  Isotopomer Analysis of Citric Acid Cycle and Gluconeogenesis in Rat Liver , 1995, The Journal of Biological Chemistry.

[106]  Guoyao Wu,et al.  Glutathione metabolism and its implications for health. , 2004, The Journal of nutrition.

[107]  Kathryn A. O’Donnell,et al.  Myc Stimulates Nuclearly Encoded Mitochondrial Genes and Mitochondrial Biogenesis , 2005, Molecular and Cellular Biology.

[108]  O. Warburg On the origin of cancer cells. , 1956, Science.

[109]  P. Rustin,et al.  Inborn errors of complex II--unusual human mitochondrial diseases. , 2002, Biochimica et biophysica acta.

[110]  G. Dunaway,et al.  A review of animal phosphofructokinase isozymes with an emphasis on their physiological role , 2004, Molecular and Cellular Biochemistry.

[111]  H. Tonami,et al.  Correlation of Glut-1 glucose transporter expression with [18F]FDG uptake in non-small cell lung cancer , 2000, European Journal of Nuclear Medicine.

[112]  M. Holness,et al.  Recent advances in mechanisms regulating glucose oxidation at the level of the pyruvate dehydrogenase complex by PDKs. , 2003, American journal of physiology. Endocrinology and metabolism.

[113]  M.-H. Lee,et al.  Roles of p53, Myc and HIF-1 in Regulating Glycolysis — the Seventh Hallmark of Cancer , 2008, Cellular and Molecular Life Sciences.

[114]  Alan J. Robinson,et al.  Fumarate Is Cardioprotective via Activation of the Nrf2 Antioxidant Pathway , 2012, Cell metabolism.

[115]  Shiyong Wu,et al.  A Small-Molecule Inhibitor of Glucose Transporter 1 Downregulates Glycolysis, Induces Cell-Cycle Arrest, and Inhibits Cancer Cell Growth In Vitro and In Vivo , 2012, Molecular Cancer Therapeutics.

[116]  C. Dang,et al.  Targeting mitochondrial glutaminase activity inhibits oncogenic transformation. , 2010, Cancer cell.

[117]  C. Deng,et al.  SIRT3 is a mitochondria-localized tumor suppressor required for maintenance of mitochondrial integrity and metabolism during stress. , 2010, Cancer cell.

[118]  L. Aaltonen,et al.  Aberrant succination of proteins in fumarate hydratase‐deficient mice and HLRCC patients is a robust biomarker of mutation status , 2011, The Journal of pathology.

[119]  M. Patel,et al.  Site Specificity of Four Pyruvate Dehydrogenase Kinase Isoenzymes toward the Three Phosphorylation Sites of Human Pyruvate Dehydrogenase* , 2001, The Journal of Biological Chemistry.

[120]  T. Nakajima,et al.  ¹⁸F-FDG uptake on PET could be a predictive marker of excision repair cross-complementation group 1 (ERCC1) expression in patients with thoracic neoplasms? , 2012, Neoplasma.

[121]  R. Moreno-Sánchez,et al.  Determining and understanding the control of glycolysis in fast‐growth tumor cells , 2006, The FEBS journal.

[122]  B. Baysal On the association of succinate dehydrogenase mutations with hereditary paraganglioma , 2003, Trends in Endocrinology & Metabolism.

[123]  Charis Eng,et al.  A role for mitochondrial enzymes in inherited neoplasia and beyond , 2003, Nature Reviews Cancer.

[124]  I. Tomlinson,et al.  The TCA cycle and tumorigenesis: the examples of fumarate hydratase and succinate dehydrogenase , 2003, Annals of medicine.

[125]  L. Huang,et al.  Carrot and stick: HIF-α engages c-Myc in hypoxic adaptation , 2008, Cell Death and Differentiation.

[126]  A. Mobasheri,et al.  Hypoxia inducible factor-1 and facilitative glucose transporters GLUT1 and GLUT3: putative molecular components of the oxygen and glucose sensing apparatus in articular chondrocytes. , 2005, Histology and histopathology.

[127]  A. Elson,et al.  The structure of the human liver-type phosphofructokinase gene. , 1990, Genomics.

[128]  R. Kletzien,et al.  Glucose‐6‐phosphate dehydrogenase: a “housekeeping” enzyme subject to tissue‐specific regulation by hormones, nutrients, and oxidant stress , 1994, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[129]  E. Gottlieb p53 guards the metabolic pathway less travelled , 2011, Nature Cell Biology.

[130]  G. Semenza,et al.  Regulation of cancer cell metabolism by hypoxia-inducible factor 1. , 2009, Seminars in cancer biology.

[131]  R. Bartrons,et al.  PFK-2/FBPase-2: maker and breaker of the essential biofactor fructose-2,6-bisphosphate. , 2001, Trends in biochemical sciences.

[132]  G. Semenza HIF-1: upstream and downstream of cancer metabolism. , 2010, Current opinion in genetics & development.

[133]  N. Illsley,et al.  Hypoxic upregulation of glucose transporters in BeWo choriocarcinoma cells is mediated by hypoxia-inducible factor-1. , 2007, American journal of physiology. Cell physiology.

[134]  P. Carmeliet,et al.  Renal Cyst Formation in Fh1-Deficient Mice Is Independent of the Hif/Phd Pathway: Roles for Fumarate in KEAP1 Succination and Nrf2 Signaling , 2011, Cancer cell.

[135]  Saroj P. Mathupala,et al.  Glucose Catabolism in Cancer Cells , 1997, The Journal of Biological Chemistry.

[136]  Saroj P. Mathupala,et al.  Mitochondrial bound type II hexokinase: a key player in the growth and survival of many cancers and an ideal prospect for therapeutic intervention. , 2002, Biochimica et biophysica acta.

[137]  L. Guarente,et al.  SirT3 suppresses hypoxia inducible factor 1α and tumor growth by inhibiting mitochondrial ROS production , 2011, Oncogene.

[138]  E. Newsholme,et al.  Maximum activities of key enzymes of glycolysis, glutaminolysis, pentose phosphate pathway and tricarboxylic acid cycle in normal, neoplastic and suppressed cells. , 1990, The Biochemical journal.

[139]  Kai Chen,et al.  Activation of p53 by Oxidative Stress Involves Platelet-derived Growth Factor-β Receptor-mediated Ataxia Telangiectasia Mutated (ATM) Kinase Activation* , 2003, Journal of Biological Chemistry.

[140]  J. Ku,et al.  Decreased pyruvate kinase M2 activity linked to cisplatin resistance in human gastric carcinoma cell lines , 2004, International journal of cancer.

[141]  Nobuyuki Tanaka,et al.  p53 regulates glucose metabolism through an IKK-NF-κB pathway and inhibits cell transformation , 2008, Nature Cell Biology.

[142]  B. Kefas,et al.  Pyruvate kinase M2 is a target of the tumor-suppressive microRNA-326 and regulates the survival of glioma cells. , 2010, Neuro-oncology.

[143]  Jun Li,et al.  Structural basis for inactivation of the human pyruvate dehydrogenase complex by phosphorylation: role of disordered phosphorylation loops. , 2008, Structure.

[144]  Guido Kroemer,et al.  Tumor cell metabolism: cancer's Achilles' heel. , 2008, Cancer cell.

[145]  T. Mak,et al.  Regulation of cancer cell metabolism , 2011, Nature Reviews Cancer.

[146]  A. Mancuso,et al.  p53 regulates biosynthesis through direct inactivation of glucose-6-phosphate dehydrogenase , 2011, Nature Cell Biology.

[147]  D. Heine-Suñer,et al.  Sequence and structure of the human 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase heart isoform gene (PFKFB2). , 1998, European journal of biochemistry.

[148]  C. Dang,et al.  Otto Warburg's contributions to current concepts of cancer metabolism , 2011, Nature Reviews Cancer.

[149]  R. Sakakibara,et al.  Characterization of a human placental fructose-6-phosphate, 2-kinase/fructose-2,6-bisphosphatase. , 1997, Journal of biochemistry.

[150]  P. Mallick,et al.  Acivicin with glutaminase regulates proliferation and invasion of human MCF-7 and OAW-42 cells--an in vitro study. , 2008, Indian journal of experimental biology.

[151]  Gregory Stephanopoulos,et al.  Quantifying Reductive Carboxylation Flux of Glutamine to Lipid in a Brown Adipocyte Cell Line* , 2008, Journal of Biological Chemistry.

[152]  Kyung-Ja Cho,et al.  Overexpression of Glut1 in lymphoid follicles correlates with false-positive (18)F-FDG PET results in lung cancer staging. , 2004, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[153]  Chi V Dang,et al.  Rethinking the Warburg effect with Myc micromanaging glutamine metabolism. , 2010, Cancer research.

[154]  R. Sakakibara,et al.  Inhibition of Tumor Cell Growth by A Specific 6-Phosphofructo-2-kinase Inhibitor, N-Bromoacetylethanolamine Phosphate, and Its Analogues , 2000, Bioscience, biotechnology, and biochemistry.

[155]  S. Nagataki,et al.  Cloning of a complete protein-coding sequence of human platelet-type phosphofructokinase isozyme from pancreatic islet. , 1994, Biochemical and biophysical research communications.

[156]  T. Kasten,et al.  Analysis of the phosphofructokinase subunits and isoenzymes in human tissues. , 1988, The Biochemical journal.

[157]  C. Harris,et al.  p53: traffic cop at the crossroads of DNA repair and recombination , 2005, Nature Reviews Molecular Cell Biology.

[158]  S. Sugano,et al.  Phosphate-activated glutaminase (GLS2), a p53-inducible regulator of glutamine metabolism and reactive oxygen species , 2010, Proceedings of the National Academy of Sciences.

[159]  A. Carruthers,et al.  Net sugar transport is a multistep process. Evidence for cytosolic sugar binding sites in erythrocytes. , 1995, Biochemistry.

[160]  G. Semenza Regulation of metabolism by hypoxia-inducible factor 1. , 2011, Cold Spring Harbor symposia on quantitative biology.

[161]  C. V. van Veelen,et al.  Subunit composition, regulatory properties, and phosphorylation of phosphofructokinase from human gliomas. , 1987, Cancer research.

[162]  R. Curi,et al.  Glutamine and glutamate—their central role in cell metabolism and function , 2003, Cell biochemistry and function.

[163]  R L Wahl,et al.  An Immunohistochemical Study , 2006 .

[164]  W. Wheaton,et al.  Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity , 2010, Proceedings of the National Academy of Sciences.

[165]  T. Nakajima,et al.  Relationship between 18F-FDG uptake on positron emission tomography and molecular biology in malignant pleural mesothelioma. , 2012, European journal of cancer.

[166]  B. Vogelstein,et al.  p53 mutations in human cancers. , 1991, Science.

[167]  D. Hebert,et al.  Glucose transporter oligomeric structure determines transporter function. Reversible redox-dependent interconversions of tetrameric and dimeric GLUT1. , 1992, The Journal of biological chemistry.

[168]  Adam L. Meadows,et al.  Estradiol stimulates the biosynthetic pathways of breast cancer cells: detection by metabolic flux analysis. , 2006, Metabolic engineering.

[169]  U. Krause,et al.  Different modes of activating phosphofructokinase, a key regulatory enzyme of glycolysis, in working vertebrate muscle. , 2001, Biochemical Society transactions.

[170]  Sam W. Lee,et al.  Influence of Induced Reactive Oxygen Species in p53-Mediated Cell Fate Decisions , 2003, Molecular and Cellular Biology.

[171]  Frank M. Sacks,et al.  IDH 1 and IDH 2 Mutations in Gliomas , 2009 .

[172]  N. C. Price,et al.  Amino acid effector binding to rabbit muscle pyruvate kinase. , 1973, Archives of biochemistry and biophysics.

[173]  P. Pedersen Voltage dependent anion channels (VDACs): a brief introduction with a focus on the outer mitochondrial compartment’s roles together with hexokinase-2 in the “Warburg effect” in cancer , 2008, Journal of Bioenergetics and Biomembranes.

[174]  Eyal Gottlieb,et al.  TIGAR, a p53-Inducible Regulator of Glycolysis and Apoptosis , 2006, Cell.

[175]  Sébastien Bonnet,et al.  A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. , 2007, Cancer cell.

[176]  K. Uyeda,et al.  Molecular cloning, sequence analysis, and expression of a human liver cDNA coding for fructose-6-P,2-kinase:fructose-2,6-bisphosphatase. , 1988, Biochemical and biophysical research communications.

[177]  R. Heinrikson,et al.  Evolution of phosphofructokinase—gene duplication and creation of new effector sites , 1984, Nature.

[178]  Chi V Dang,et al.  Multifaceted roles of glycolytic enzymes. , 2005, Trends in biochemical sciences.

[179]  P. Pandolfi,et al.  SIRT3 opposes reprogramming of cancer cell metabolism through HIF1α destabilization. , 2011, Cancer cell.

[180]  James L. Park,et al.  A GSK-3/TSC2/mTOR pathway regulates glucose uptake and GLUT1 glucose transporter expression. , 2008, American journal of physiology. Cell physiology.

[181]  A. Levine,et al.  Surfing the p53 network , 2000, Nature.

[182]  Ralph J Deberardinis,et al.  Brick by brick: metabolism and tumor cell growth. , 2008, Current opinion in genetics & development.

[183]  C. Thompson,et al.  Akt maintains cell size and survival by increasing mTOR-dependent nutrient uptake. , 2002, Molecular biology of the cell.

[184]  A. Paetau,et al.  Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer , 2002, Nature Genetics.

[185]  I. Kurland,et al.  6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase: a metabolic signaling enzyme. , 1995, Annual review of biochemistry.

[186]  D. Burstein,et al.  GLUT1 glucose transporter expression in colorectal carcinoma , 1998, Cancer.

[187]  Tina Mlakar,et al.  Citrate Inhibition-Resistant Form of 6-Phosphofructo-1-Kinase from Aspergillus niger , 2006, Applied and Environmental Microbiology.

[188]  P. Rustin,et al.  The R22X mutation of the SDHD gene in hereditary paraganglioma abolishes the enzymatic activity of complex II in the mitochondrial respiratory chain and activates the hypoxia pathway. , 2001, American journal of human genetics.

[189]  Li Wei,et al.  Hypoxia regulation of facilitated glucose transporter-1 and glucose transporter-3 in mouse chondrocytes mediated by HIF-1alpha. , 2008, Joint, bone, spine : revue du rhumatisme.

[190]  M. Armoni,et al.  The Tumor Suppressor p53 Down-Regulates Glucose Transporters GLUT1 and GLUT4 Gene Expression , 2004, Cancer Research.

[191]  C. Eng,et al.  Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. , 2004, JAMA.

[192]  Chi V Dang,et al.  MYC on the Path to Cancer , 2012, Cell.

[193]  G. Semenza Expression of hypoxia-inducible factor 1: mechanisms and consequences. , 2000, Biochemical pharmacology.

[194]  B. Lemire,et al.  The Quaternary Structure of the Saccharomyces cerevisiae Succinate Dehydrogenase , 2004, Journal of Biological Chemistry.

[195]  R. Bhat,et al.  Differential Behavior of Missense Mutations in the Intersubunit Contact Domain of the Human Pyruvate Kinase M2 Isozyme* , 2009, Journal of Biological Chemistry.

[196]  P. Verde,et al.  Glucose-6-phosphate dehydrogenase plays a crucial role in protection from redox-stress-induced apoptosis , 2004, Cell Death and Differentiation.

[197]  C. Hellerbrand,et al.  GLUT1 as a therapeutic target in hepatocellular carcinoma , 2009, Expert opinion on therapeutic targets.

[198]  Ralph J DeBerardinis,et al.  Role of Glutamine in Cancer: Therapeutic and Imaging Implications , 2011, The Journal of Nuclear Medicine.

[199]  Takashi Tsukamoto,et al.  Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells. , 2012, Cell metabolism.

[200]  C. Stout,et al.  Crystal structures of aconitase with trans-aconitate and nitrocitrate bound. , 1993, Journal of molecular biology.

[201]  K. Kinzler,et al.  A model for p53-induced apoptosis , 1997, Nature.

[202]  T. Tanaka,et al.  Structure of the entire human muscle phosphofructokinase-encoding gene: a two-promoter system. , 1991, Gene.

[203]  P. Rustin,et al.  Mutations in the SDHB gene are associated with extra-adrenal and/or malignant phaeochromocytomas. , 2003, Cancer research.

[204]  M. Legiša,et al.  Posttranslational Modification of 6-phosphofructo-1-kinase as an Important Feature of Cancer Metabolism , 2011, PloS one.