Metabolic changes in cancer: beyond the Warburg effect

On the origin of cancer cells

Warburg, O. (1956) · Science · doi:10.1126/science.123.3191.309 · Cited by 13,425 · see citing works

Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension.

Wang, G. L., Jiang, B. H., Rue, E. A., & Semenza, G. L. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.12.5510 · Cited by 6,212 · see citing works

Why Do Cancers Have High Aerobic Glycolysis?

Gatenby, R. A., & Gillies, R. J. (2004) · Nature reviews. Cancer · doi:10.1038/nrc1478 · Cited by 4,784 · see citing works

Cancer-associated IDH1 mutations produce 2-hydroxyglutarate

Dang, L., White, D. W., Gross, S., Bennett, B. D., Bittinger, M. A., Driggers, E. M., Fantin, V. R., Jang, H. G., Jin, S., Keenan, M. C., et al. (2009) · Nature · doi:10.1038/nature08617 · Cited by 4,154 · see citing works

HIF-1-mediated expression of pyruvate dehydrogenase kinase: A metabolic switch required for cellular adaptation to hypoxia

Kim, J.-W., Tchernyshyov, I., Semenza, G. L., & Dang, C. V. (2006) · Cell Metabolism · doi:10.1016/j.cmet.2006.02.002 · Cited by 3,905 · see citing works

Hypoxia-inducible factors in physiology and medicine

Semenza, G. L. (2012) · Cell · doi:10.1016/j.cell.2012.01.021 · Cited by 3,645 · see citing works

On Respiratory Impairment in Cancer Cells

Warburg, O. H. (1956) · Science · doi:10.1126/science.124.3215.269 · Cited by 3,472 · see citing works

Otto Warburg's contributions to current concepts of cancer metabolism

Koppenol, W. H., Bounds, P. L., & Dang, C. V. (2011) · Nature Reviews Cancer · doi:10.1038/nrc3038 · Cited by 3,427 · see citing works

MYC on the Path to Cancer

Dang, C. V. (2012) · Cell · doi:10.1016/j.cell.2012.03.003 · Cited by 3,390 · see citing works

Oncometabolite 2-Hydroxyglutarate Is a Competitive Inhibitor of α-Ketoglutarate-Dependent Dioxygenases

Xu, W., Yang, H., Liu, Y., Yang, Y., Wang, P., Kim, S.-H., Ito, S., Yang, C., Wang, P., Xiao, M.-T., et al. (2011) · Cancer Cell · doi:10.1016/j.ccr.2010.12.014 · Cited by 2,875 · see citing works

The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth

Christofk, H. R., Vander Heiden, M. G., Harris, M. H., Ramanathan, A., Gerszten, R. E., Wei, R., Fleming, M. D., Schreiber, S. L., & Cantley, L. C. (2008) · Nature · doi:10.1038/nature06734 · Cited by 2,820 · see citing works

Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts

Nakagawa, M., Koyanagi, M., Tanabe, K., Takahashi, K., Ichisaka, T., Aoi, T., Okita, K., Mochiduki, Y., Takizawa, N., & Yamanaka, S. (2007) · Nature Biotechnology · doi:10.1038/nbt1374 · Cited by 2,781 · see citing works

Leukemic IDH1 and IDH2 Mutations Result in a Hypermethylation Phenotype, Disrupt TET2 Function, and Impair Hematopoietic Differentiation

Figueroa, M. E., Abdel-Wahab, O., Lu, C., Ward, P. S., Patel, J., Shih, A., Li, Y., Bhagwat, N., Vasanthakumar, A., Fernandez, H. F., et al. (2010) · Cancer Cell · doi:10.1016/j.ccr.2010.11.015 · Cited by 2,766 · see citing works

A model for p53-induced apoptosis

Polyak, K., Xia, Y., Zweier, J. L., Kinzler, K. W., & Vogelstein, B. (1997) · Nature · doi:10.1038/38525 · Cited by 2,500 · see citing works

c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism

Gao, P., Tchernyshyov, I., Chang, T.-C., Lee, Y.-S., Kita, K., Ochi, T., Zeller, K. I., De Marzo, A. M., Van Eyk, J. E., Mendell, J. T., et al. (2009) · Nature · doi:10.1038/nature07823 · Cited by 2,124 · see citing works

Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-α prolyl hydroxylase

Selak, M. A., Armour, S. M., MacKenzie, E. D., Boulahbel, H., Watson, D. G., Mansfield, K. D., Pan, Y., Simon, M. C., Thompson, C. B., & Gottlieb, E. (2005) · Cancer Cell · doi:10.1016/j.ccr.2004.11.022 · Cited by 2,108 · see citing works

TIGAR, a p53-Inducible Regulator of Glycolysis and Apoptosis

Bensaad, K., Tsuruta, A., Selak, M. A., Vidal, M. N. C., Nakano, K., Bartrons, R., Gottlieb, E., & Vousden, K. H. (2006) · Cell · doi:10.1016/j.cell.2006.05.036 · Cited by 2,019 · see citing works

IDH mutation impairs histone demethylation and results in a block to cell differentiation

Lu, C., Ward, P. S., Kapoor, G. S., Rohle, D., Turcan, S., Abdel-Wahab, O., Edwards, C. R., Khanin, R., Figueroa, M. E., Melnick, A., et al. (2012) · Nature · doi:10.1038/nature10860 · Cited by 1,985 · see citing works

Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1.

Semenza, G., Roth, P. H., Fang, H. M., & Wang, G. L. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)31580-6 · Cited by 1,892 · see citing works

p53 Regulates Mitochondrial Respiration

Matoba, S., Kang, J.-G., Patino, W. D., Wragg, A., Boehm, M., Gavrilova, O., Hurley, P. J., Bunz, F., & Hwang, P. M. (2006) · Science · doi:10.1126/science.1126863 · Cited by 1,650 · see citing works

Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer

The Multiple Leiomyoma Consortium (2002) · Nature Genetics · doi:10.1038/ng849 · Cited by 1,635 · see citing works

Pyruvate Kinase M2 Is a PHD3-Stimulated Coactivator for Hypoxia-Inducible Factor 1

Luo, W., Hu, H., Chang, R., Zhong, J., Knabel, M., O'Meally, R., Cole, R. N., Pandey, A., & Semenza, G. L. (2011) · Cell · doi:10.1016/j.cell.2011.03.054 · Cited by 1,463 · see citing works

Evidence that glutamine, not sugar, is the major energy source for cultured HeLa cells.

Reitzer, L. J., Wice, B. M., & Kennell, D. (1979) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)30124-2 · Cited by 1,240 · see citing works

Inhibition of Pyruvate Kinase M2 by Reactive Oxygen Species Contributes to Cellular Antioxidant Responses

Anastasiou, D., Poulogiannis, G., Asara, J. M., Boxer, M. B., Jiang, J., Shen, M., Bellinger, G., Sasaki, A. T., Locasale, J. W., Auld, D. S., et al. (2011) · Science · doi:10.1126/science.1211485 · Cited by 1,196 · see citing works

HnRNP proteins controlled by c-Myc deregulate pyruvate kinase mRNA splicing in cancer

David, C. J., Chen, M., Assanah, M., Canoll, P., & Manley, J. L. (2010) · Nature · doi:10.1038/nature08697 · Cited by 1,179 · see citing works

The role of Tet3 DNA dioxygenase in epigenetic reprogramming by oocytes

Gu, T., Guo, F., Yang, H., Wu, H.-P., Xu, G., Liu, W., Xie, Z.-G., Shi, L., He, X., Jin, S., et al. (2011) · Nature · doi:10.1038/nature10443 · Cited by 1,144 · see citing works

Glioma-Derived Mutations in <i>IDH1</i> Dominantly Inhibit IDH1 Catalytic Activity and Induce HIF-1α

Zhao, S., Lin, Y., Xu, W., Jiang, W., Zha, Z., Wang, P., Yu, W., Li, Z., Gong, L., Peng, Y., et al. (2009) · Science · doi:10.1126/science.1170944 · Cited by 1,119 · see citing works

c-Myc transactivation of <i>LDH-A</i> : Implications for tumor metabolism and growth

Shim, H., Dolde, C., Lewis, B. C., Wu, C.-S., Dang, G., Jungmann, R. A., Dalla-Favera, R., & Dang, C. V. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.13.6658 · Cited by 1,092 · see citing works

Nuclear PKM2 regulates β-catenin transactivation upon EGFR activation

Yang, W., Xia, Y., Ji, H., Zheng, Y., Liang, J., Huang, W., Gao, X., Aldape, K., & Lu, Z. (2011) · Nature · doi:10.1038/nature10598 · Cited by 1,033 · see citing works

<i>IDH1</i> and <i>IDH2</i> mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours

Amary, M. F., Bacsi, K., Maggiani, F., Damato, S., Halai, D., Berisha, F., Pollock, R., O'Donnell, P., Grigoriadis, A., Diss, T., et al. (2011) · The Journal of Pathology · doi:10.1002/path.2913 · Cited by 1,023 · see citing works

Pyruvate kinase M2 is a phosphotyrosine-binding protein

Christofk, H. R., Vander Heiden, M. G., Wu, N., Asara, J. M., & Cantley, L. C. (2008) · Nature · doi:10.1038/nature06667 · Cited by 995 · see citing works

p53 and metabolism

Vousden, K. H., & Ryan, K. M. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2715 · Cited by 959 · see citing works

HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: Novel role of fumarate in regulation of HIF stability

Isaacs, J. S., Jung, Y. J., Mole, D. R., Lee, S., Torres-Cabala, C., Chung, Y.-L., Merino, M., Trepel, J., Zbar, B., Toro, J., et al. (2005) · Cancer Cell · doi:10.1016/j.ccr.2005.06.017 · Cited by 958 · see citing works

PKM2 Phosphorylates Histone H3 and Promotes Gene Transcription and Tumorigenesis

Yang, W., Xia, Y., Hawke, D., Li, X., Liang, J., Xing, D., Aldape, K., Hunter, T., Alfred Yung, W. K., & Lu, Z. (2012) · Cell · doi:10.1016/j.cell.2012.07.018 · Cited by 846 · see citing works

Fuel feeds function: energy metabolism and the T-cell response

Fox, C. J., Hammerman, P. S., & Thompson, C. B. (2005) · Nature reviews. Immunology · doi:10.1038/nri1710 · Cited by 841 · see citing works

Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis

Anastasiou, D., Yu, Y., Israelsen, W. J., Jiang, J.-K., Boxer, M. B., Hong, B. S., Tempel, W., Dimov, S., Shen, M., Jha, A., et al. (2012) · Nature Chemical Biology · doi:10.1038/nchembio.1060 · Cited by 816 · see citing works

HIF and c-Myc: Sibling Rivals for Control of Cancer Cell Metabolism and Proliferation

Gordan, J. D., Thompson, C. B., & Simon, M. C. (2007) · Cancer Cell · doi:10.1016/j.ccr.2007.07.006 · Cited by 796 · see citing works

Tyrosine Phosphorylation Inhibits PKM2 to Promote the Warburg Effect and Tumor Growth

Hitosugi, T., Kang, S., Vander Heiden, M. G., Chung, T.-W., Elf, S., Lythgoe, K., Dong, S., Lonial, S., Wang, X., Chen, G. Z., et al. (2009) · Science Signaling · doi:10.1126/scisignal.2000431 · Cited by 784 · see citing works

The Tumor Suppressor p53 Down-Regulates Glucose Transporters GLUT1 and GLUT4 Gene Expression

Bar‐Yoseph, F., Armoni, M., & Karnieli, E. (2004) · Cancer Research · doi:10.1158/0008-5472.can-03-0846 · Cited by 728 · see citing works

Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation

Koivunen, P., Lee, S., Duncan, C. G., Lopez, G., Lu, G., Ramkissoon, S., Losman, J. A., Joensuu, P., Bergmann, U., Gross, S., et al. (2012) · Nature · doi:10.1038/nature10898 · Cited by 727 · see citing works

<i>SDH5</i> , a Gene Required for Flavination of Succinate Dehydrogenase, Is Mutated in Paraganglioma

Hao, H.-X., Khalimonchuk, O., Schraders, M., Dephoure, N., Bayley, J.-P., Kunst, H., Devilee, P., Cremers, C. W. R. J., Schiffman, J. D., Bentz, B. G., et al. (2009) · Science · doi:10.1126/science.1175689 · Cited by 702 · see citing works

Metabolic Regulation of Epigenetics

Lu, C., & Thompson, C. B. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.06.001 · Cited by 699 · see citing works

A Positron-Emission Transaxial Tomograph for Nuclear Imaging (PETT)

Ter‐Pogossian, M. M., Phelps, M. E., Hoffman, E. J., & Mullani, N. A. (1975) · Radiology · doi:10.1148/114.1.89 · Cited by 682 · see citing works

Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer

King, A., Selak, M. A., & Gottlieb, E. (2006) · Oncogene · doi:10.1038/sj.onc.1209594 · Cited by 672 · see citing works

The interplay between MYC and HIF in cancer

Dang, C. V., Kim, J., Gao, P., & Yustein, J. T. (2007) · Nature reviews. Cancer · doi:10.1038/nrc2274 · Cited by 614 · see citing works

Acetylation Targets the M2 Isoform of Pyruvate Kinase for Degradation through Chaperone-Mediated Autophagy and Promotes Tumor Growth

Lv, L., Dong, L., Zhao, D., Lin, R., Chu, Y., Zhang, H., Zha, Z., Liu, Y., Li, Z., Xu, Y., et al. (2011) · Molecular Cell · doi:10.1016/j.molcel.2011.04.025 · Cited by 605 · see citing works

IDH1 mutations are present in the majority of common adult gliomas but rare in primary glioblastomas

Ichimura, K., Pearson, D. M., Kocialkowski, S., Bäcklund, L. M., Chan, R., Jones, D., & Collins, V. P. (2009) · Neuro-Oncology · doi:10.1215/15228517-2009-025 · Cited by 593 · see citing works

On respiratory impairment in cancer cells

Weinhouse, S. (1956) · Science · doi:10.1126/science.124.3215.267 · Cited by 554 · see citing works

Aerobic glycolysis by proliferating cells: a protective strategy against reactive oxygen species ¹

Brand, K. A., & Hermfisse, U. (1997) · The FASEB Journal · doi:10.1096/fasebj.11.5.9141507 · Cited by 401 · see citing works

SDH mutations in cancer

Bardella, C., Pollard, P. J., & Tomlinson, I. (2011) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2011.07.003 · Cited by 395 · see citing works

The role of high rates of glycolysis and glutamine utilization in rapidly dividing cells

Newsholme, E. A., Crabtree, B., & Ardawi, M. S. (1985) · Bioscience Reports · doi:10.1007/bf01116556 · Cited by 364 · see citing works

Modulation of intracellular ROS levels by TIGAR controls autophagy

Bensaad, K., Cheung, E. C., & Vousden, K. H. (2009) · The EMBO Journal · doi:10.1038/emboj.2009.242 · Cited by 361 · see citing works

PFK-2/FBPase-2: maker and breaker of the essential biofactor fructose-2,6-bisphosphate

Okar, D. A., Lange, A. J., Manzano, À., Navarro‐Sabaté, À., Riera, L., & Bartrons, R. (2001) · Trends in Biochemical Sciences · doi:10.1016/s0968-0004(00)01699-6 · Cited by 356 · see citing works

Prevalence of SDHB, SDHC, and SDHD germline mutations in clinic patients with head and neck paragangliomas

Baysal, B. E., Willett-Brozick, J. E., Lawrence, E. C., Drovdlic, C. M., Savul, S. A., McLeod, D. R., Yee, H. A., Brackmann, D. E., Slattery, W. H., Myers, E. N., et al. (2002) · Journal of Medical Genetics · doi:10.1136/jmg.39.3.178 · Cited by 336 · see citing works

Glucose Deprivation‐Induced Oxidative Stress in Human Tumor Cells: A Fundamental Defect in Metabolism?

Spitz, D. R., Sim, J. E., Ridnour, L. A., Galoforo, S., & Lee, Y. J. (2000) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2000.tb06199.x · Cited by 331 · see citing works

Human pyruvate kinase M2: A multifunctional protein

Gupta, V., & Bamezai, R. N. K. (2010) · Protein Science · doi:10.1002/pro.505 · Cited by 318 · see citing works

Glycolysis, glutaminolysis and cell proliferation

McKeehan, W. L. (1982) · Cell Biology International Reports · doi:10.1016/0309-1651(82)90125-4 · Cited by 305 · see citing works

SDH mutations in tumorigenesis and inherited endocrine tumours: lesson from the phaeochromocytoma–paraganglioma syndromes

Pasini, B., & Stratakis, C. A. (2009) · Journal of Internal Medicine · doi:10.1111/j.1365-2796.2009.02111.x · Cited by 268 · see citing works

No evidence for a shift in pyruvate kinase PKM1 to PKM2 expression during tumorigenesis

Bluemlein, K., Grüning, N., Feichtinger, R. G., Lehrach, H. R., Kofler, B., & Ralser, M. (2011) · Oncotarget · doi:10.18632/oncotarget.278 · Cited by 254 · see citing works

A ribonucleotide reductase gene is a transcriptional target of p53 and p73

Nakano, K., Bálint, É., Ashcroft, M. A., & Vousden, K. H. (2000) · Oncogene · doi:10.1038/sj.onc.1203774 · Cited by 231 · see citing works

Hypoxia-inducible factors and their roles in energy metabolism

Goda, N., & Kanai, M. (2012) · International Journal of Hematology · doi:10.1007/s12185-012-1069-y · Cited by 213 · see citing works

Mutations in the d-2-Hydroxyglutarate Dehydrogenase Gene Cause d-2-Hydroxyglutaric Aciduria

Struys, E. A., Salomons, G. S., Achouri, Y., Van Schaftingen, E., Grosso, S., Craigen, W. J., Verhoeven, N. M., & Jakobs, C. (2005) · The American Journal of Human Genetics · doi:10.1086/427890 · Cited by 172 · see citing works

Activation of p53 by Oxidative Stress Involves Platelet-derived Growth Factor-β Receptor-mediated Ataxia Telangiectasia Mutated (ATM) Kinase Activation

Chen, K., Albano, A., Ho, A., & Keaney, J. F. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m304423200 · Cited by 95 · see citing works

Iron- and 2-oxoglutarate-dependent Dioxygenases: an emerging group of molecular targets for nickel toxicity and carcinogenicity

Chen, H., & Costa, M. (2008) · BioMetals · doi:10.1007/s10534-008-9190-3 · Cited by 73 · see citing works

A Recurrent Stop-Codon Mutation in Succinate Dehydrogenase Subunit B Gene in Normal Peripheral Blood and Childhood T-Cell Acute Leukemia

Baysal, B. E. (2007) · PLoS ONE · doi:10.1371/journal.pone.0000436 · Cited by 50 · see citing works

Coordination of glucose and glutamine utilization by an expanded Myc network

Kaadige, M. R., Elgort, M., & Ayer, D. E. (2010) · Transcription · doi:10.4161/trns.1.1.12142 · Cited by 31 · see citing works

Role of Iron (II)-2-Oxoglutarate-dependent Dioxygenases in the Generation of Hypoxia-induced Phosphatidic Acid through HIF-1/2 and von Hippel-Lindau-independent Mechanisms

Martı́n-Puig, S., Temes, E., Olmos, G., Jones, D., Aragonés, J., & Landázuri, M. O. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m310658200 · Cited by 11 · see citing works

Adult manifestation of l -2-hydroxyglutarate dehydrogenase deficiency by a novel mutation

Sühs, K., Erdmann, P., Shamdeen, M. G., Papanagiotou, P., & Dillmann, U. (2012) · Neurology · doi:10.1212/wnl.0b013e31824f8033 · Cited by 2 · see citing works

Succinate: a metabolic signal in inflammation

Mills, E., & O’Neill, L. A. J. (2014) · Trends in Cell Biology · doi:10.1016/j.tcb.2013.11.008 · Cited by 741 · see citing works

Coupling Krebs cycle metabolites to signalling in immunity and cancer

Ryan, D. G., Murphy, M. P., Frezza, C., Prag, H. A., Chouchani, E. T., O’Neill, L. A., & Mills, E. L. (2018) · Nature Metabolism · doi:10.1038/s42255-018-0014-7 · Cited by 398 · see citing works

The metabolic landscape of lung cancer: New insights in a disturbed glucose metabolism

Vanhove, K., Graulus, G.-J., Mesotten, L., Thomeer, M., Derveaux, E., Noben, J.-P., Guedens, W., & Adriaensens, P. (2019) · Frontiers in Oncology · doi:10.3389/fonc.2019.01215 · Cited by 147 · see citing works

Overcoming the Warburg Effect: Is it the key to survival in sepsis?

Bar‐Or, D., Carrick, M. M., Tanner, A. H., Lieser, M. J., Rael, L. T., & Brody, E. N. (2017) · Journal of Critical Care · doi:10.1016/j.jcrc.2017.09.012 · Cited by 72 · see citing works

An Anti-tumorigenic Role of the Warburg Effect at Emergence of Transformed Cells

Ishibashi, K., Egami, R., Nakai, K., & Kon, S. (2018) · Cell Structure and Function · doi:10.1247/csf.18018 · Cited by 6 · see citing works

Oncogenic alterations of metabolism and the Warburg effect

Kim, J., Gardner, L. B., & Dang, C. V. (2005) · Drug Discovery Today Disease Mechanisms · doi:10.1016/j.ddmec.2005.04.001 · Cited by 23 · see citing works

Isocitrate dehydrogenase (IDH), succinate dehydrogenase (SDH), fumarate hydratase (FH): three players for one phenotype in cancer?

Laurenti, G., & Tennant, D. A. (2016) · Biochemical Society Transactions · doi:10.1042/bst20160099 · Cited by 79 · see citing works

Warburg effect in Gynecologic cancers

Kobayashi, Y., Banno, K., Kunitomi, H., Takahashi, T., Takeda, T., Nakamura, K., Tsuji, K., Tominaga, E., & Aoki, D. (2018) · Journal of obstetrics and gynaecology research · doi:10.1111/jog.13867 · Cited by 61 · see citing works