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Cited by 16,197Cancer, Hypoxia, and MetabolismMetabolism, Diabetes, and CancerCancer and biochemical research

Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation

Open access
Vander Heiden, Matthew G., Cantley, Lewis C., Thompson, Craig B.·2009·Science
DOI 10.1126/science.1160809PMC PMC2849637
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Abstract

Fuel Economy for Growing Cells: Sophisticated 21st-century analyses of the signaling pathways that control cell growth have led researchers back to the seminal work of Otto Warburg, who discovered in the 1920s that tumor cells generate their energy in an unusual way—by switching from mitochondrial respiration to glycolysis. The advantage conferred by this metabolic switch is puzzling because mitochondrial respiration is a more efficient way to produce ATP. Vander Heiden et al. (p. 1029 ) review arguments that rapidly growing cells have critical metabolic requirements that extend beyond ATP and that a better understanding of these requirements may shed new light on the “Warburg effect” and ultimately lead to new therapies for cancer.

Integrity signals

Registry

Crossref · 10.1126/science.1160809

Cites

47 of 47 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 68 cited sources checked · 0 supported · 0 flagged

  • Findingreasoning

    The 35-fold asymmetry is only partially compensated by consumption of 3 glucose molecules in acetyl-CoA production for the acyl chain carbon.

    “This 35-fold asymmetry is only partially compensated by the consumption of 3 glucose molecules in acetyl-CoA production to satisfy the carbon requirement of the acyl chain itself.”
    Quote in the paperSubstantial claim
  • Interpretationreasoning

    Some glucose must be diverted to macromolecular precursors such as acetyl-CoA for fatty acids, glycolytic intermediates for nonessential amino acids, and ribose for nucleotides.

    “Some glucose must be diverted to macromolecular precursors such as acetyl-CoA for fatty acids, glycolytic intermediates for nonessential amino acids, and ribose for nucleotides.”
    Quote in the paperSubstantial claim
  • Premisecitation

    Inhibiting LDH activity impairs cell proliferation.

    “Inhibiting LDH activity impairs cell proliferation (6)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [6] Fantin VR St-Pierre J Leder P Cancer Cell 9 425 2006 16766262

      Not checked in the free run.

  • Premisereasoning

    Most carbon for fatty acid synthesis is derived from glucose.

    “Most of the carbon for fatty acid synthesis is derived from glucose.”
    Quote in the paperSubstantial claim
  • Premisecitation

    Normal proliferating cells can arrest and reactivate catabolic metabolism when ATP production from glucose is compromised.

    “Normal proliferating cells can also undergo cell cycle arrest and reactivate catabolic metabolism when their ability to produce ATP from glucose is compromised (12, 13)”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [12] Shaw RJ Proc Natl Acad Sci USA 101 3329 2004 14985505 PMC373461

      Not checked in the free run.

    • cites [13] Lum JJ Cell 120 237 2005 15680329

      Not checked in the free run.

  • May combine two claims. 19
  • Classified as probably not a substantial claim. 6

  • May combine two claims.

    Findingreasoning

    To make a 16-carbon fatty acyl chain, one glucose provides five times the ATP required, while seven glucose molecules are needed for the NADPH required.

    “to make a 16-carbon fatty acyl chain, a single glucose molecule can provide five times the ATP required, whereas 7 glucose molecules are needed to generate the NADPH required”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Palmitate synthesis requires 7 ATP, 16 carbons from 8 acetyl-CoA, and 28 electrons from 14 NADPH.

    “synthesis of palmitate, a major constituent of cellular membranes, requires 7 molecules of ATP, 16 carbons from 8 molecules of acetyl-CoA (coenzyme A), and 28 electrons from 14 molecules of NADPH”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [8] Lehninger AL Nelson DL Cox MM Principles of Biochemistry Worth New York 2 1993

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Synthesis of acetyl-CoA from citrate requires ACL, and disruption of ACL impairs tumor growth.

    “Synthesis of acetyl-CoA from citrate requires the enzyme ATP citrate lyase (ACL), and disruption of ACL impairs tumor growth (18).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] Hatzivassiliou G Cancer Cell 8 311 2005 16226706

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Proliferating cells have important metabolic requirements that extend beyond ATP.

    “A second possible explanation for the switch to aerobic glycolysis, discussed in detail below, is that proliferating cells have important metabolic requirements that extend beyond ATP.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Growth factor signaling regulates pyruvate kinase activity and modulates carbon flux through later glycolysis.

    “Growth factor signaling also regulates the activity of the glycolytic enzyme pyruvate kinase and modulates flux of carbon through the later steps of glycolysis (9, 17).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [9] Christofk HR Nature 452 230 2008 18337823

      Not checked in the free run.

    • cites [17] Christofk HR Vander Heiden MG Wu N Asara JM Cantley LC Nature 452 181 2008 18337815

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A glucose molecule can generate up to 36 ATP, or 30 ATP and 2 NADPH, or provide 6 carbons for macromolecular synthesis.

    “A glucose molecule can generate up to 36 ATPs, or 30 ATPs and 2 NADPHs [if diverted into the pentose phosphate shunt (8, 15)], or provide 6 carbons for macromolecular synthesis.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [8] Lehninger AL Nelson DL Cox MM Principles of Biochemistry Worth New York 2 1993

      Not checked in the free run.

    • cites [15] Possibly up to four NADPH molecules per glucose can be produced if the products of the pentose phosphate shunt are metabolized via the TCA cycle and malic enzyme or cytosolic isocitrate dehydrogenase 1 (IDH1) to generate two additional NADPH molecules.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Aerobic glycolysis yields only 2 ATP per glucose, while complete oxidation via oxidative phosphorylation yields up to 36 ATP.

    “The metabolism of glucose to lactate generates only 2 ATPs per molecule of glucose, whereas oxidative phosphorylation generates up to 36 ATPs upon complete oxidation of one glucose molecule (8).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [8] Lehninger AL Nelson DL Cox MM Principles of Biochemistry Worth New York 2 1993

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Glucose withdrawal induces cell death indistinguishable from growth factor withdrawal, possibly contributing to oncogene addiction.

    “Glucose withdrawal induces cell death in a manner indistinguishable from that seen upon withdrawal of growth factor signaling, a phenomenon that may contribute to “oncogene addiction” (22).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [22] Vander Heiden MG Mol Cell Biol 21 5899 2001 11486029 PMC87309

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PI3K signaling through AKT can regulate glucose transporter expression, enhance glucose capture by hexokinase, and stimulate phosphofructokinase activity.

    “PI3K signaling through AKT can regulate glucose transporter expression, enhance glucose capture by hexokinase, and stimulate phosphofructokinase activity (2)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [2] Deberardinis RJ Lum JJ Hatzivassiliou G Thompson CB Cell Metab 7 11 2008 18177721

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Small molecules that disrupt PI3K signaling decrease tumor glucose uptake by FDG-PET, and the ability to inhibit tumor FDG uptake correlates with tumor regression.

    “Small molecules that disrupt PI3K signaling lead to decreased glucose uptake by tumors as measured by 18F-deoxyglucose positron emission tomography (FDG-PET), and the ability to inhibit tumor FDG uptake correlates with tumor regression (21).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [21] Engelman JA Nat Med 14 1351 2008 19029981 PMC2683415

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    p53 expression controls metabolic genes and alters glucose utilization.

    “p53 expression controls metabolic genes and alters glucose utilization”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    TIGAR, a gene induced by p53, inhibits phosphofructokinase, redirects glucose toward the pentose phosphate shunt, and produces NADPH.

    “Expression of TIGAR, a gene induced by p53, leads to inhibition of phosphofructokinase, redirection of glucose toward the pentose phosphate shunt, and NADPH production (34).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [34] Bensaad K Cell 126 107 2006 16839880

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Dumping excess carbon as lactate may allow faster incorporation of carbon into biomass, facilitating rapid cell division.

    “Possibly the dumping of excess carbon as lactate is effective because it allows faster incorporation of carbon into biomass, which in turn facilitates rapid cell division.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Oncogenic Ras causes alterations in glucose metabolism but causes senescence when expressed in cells without a cooperating oncogene.

    “oncogenic Ras causes alterations in glucose metabolism (35) but causes senescence when expressed in cells without a cooperating oncogene (36)”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [35] Chiaradonna F Oncogene 25 5391 2006 16607279

      Not checked in the free run.

    • cites [36] Serrano M Lin AW McCurrach ME Beach D Lowe SW Cell 88 593 1997 9054499

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The Cori cycle in the liver can recycle lactate from proliferating tissues to glucose, and analogous pathways recycle alanine.

    “The Cori cycle in the liver can recycle lactate generated from actively proliferating tissues to glucose, and analogous pathways exist to recycle the alanine generated from “inefficient” glutamine metabolism (8).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] Lehninger AL Nelson DL Cox MM Principles of Biochemistry Worth New York 2 1993

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    IDH1 and IDH2 couple the interconversion of cytosolic isocitrate and α-ketoglutarate in an NADP+/NADPH-dependent reaction.

    “IDH1 and IDH2 couple the interconversion of cytosolic isocitrate and α-ketoglutarate in an NADP+/NADPH-dependent reaction.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Mitochondrial oxidative phosphorylation is the major cellular source of ROS production.

    “Mitochondrial oxidative phosphorylation is the major cellular source of ROS production.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Leukemic cells are highly glycolytic yet reside within the bloodstream at higher oxygen tensions than cells in most normal tissues.

    “leukemic cells are highly glycolytic (40, 41), yet these cells reside within the bloodstream at higher oxygen tensions than cells in most normal tissues”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [40] Gottschalk S Anderson N Hainz C Eckhardt SG Serkova NJ Clin Cancer Res 10 6661 2004 15475456

      Not checked in the free run.

    • cites [41] Elstrom RL Cancer Res 64 3892 2004 15172999

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationreasoning

    One function of oncogenic pathways is to drive cell-autonomous nutrient uptake and program proliferative metabolism, whereas one function of tumor suppressor pathways is to prevent nutrient utilization for anabolic processes.

    “Perhaps one function of oncogenic pathways is to drive cell-autonomous nutrient uptake and program proliferative metabolism, whereas one function of tumor suppressor pathways is to prevent nutrient utilization for anabolic processes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Available evidence suggests that tumor hypoxia is a late-occurring event and may not be a major contributor to the switch to aerobic glycolysis by cancer cells.

    “the available evidence suggests that it is a late-occurring event that may not be a major contributor in the switch to aerobic glycolysis by cancer cells”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    There is mounting evidence for cross-talk between signaling pathways and metabolic control in every multicellular organism studied.

    “There is mounting evidence for cross-talk between signaling pathways and metabolic control in every multicellular organism studied.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Metformin and the more potent related compound Phenformin activate AMPK in cells.

    “Metformin and the more potent related compound Phenformin activate AMPK in cells”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Metformin may offer a possible benefit in cancer prevention as well as improved outcomes when used with other cancer therapies.

    “the widely used diabetes drug metformin may offer a possible benefit in cancer prevention as well as improved outcomes when used with other cancer therapies (44)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [44] Evans JM Donnelly LA Emslie-Smith AM Alessi DR Morris AD BMJ 330 1304 2005 15849206 PMC558205

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    A large fraction of human cancer is dependent on aberrant signaling through the PI3K/Akt pathway.

    “a large fraction of human cancer is dependent on aberrant signaling through the PI3K/Akt pathway”
    Quote in the paperNot a substantial claim
24 of 24

  • The paper relies on this without support.

    For most mammalian cells in culture, glucose and glutamine are the only two molecules catabolized in appreciable quantities.

    “For most mammalian cells in culture, the only two molecules catabolized in appreciable quantities are glucose and glutamine.”

  • The paper relies on this without support.

    Nutrients are not limiting for most proliferating cells.

    “For most proliferating cells, nutrients are not limiting so there is no selective pressure to optimize metabolism for ATP yield.”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • High levels of ROS generated by ongoing aerobic glycolysis followed by pyruvate oxidation in mitochondria (the Warburg effect) increase receptor and oncogene activity and induce genetic instability.

    “high levels of ROS generated by ongoing aerobic glycolysis followed by pyruvate oxidation in mitochondria (the Warburg effect), increase receptor and oncogene activity, and the stimulation of growth factor-dependent pathways or oxidizing enzymes induce genetic instability3,4.”

    From ROS in cancer therapy: the bright side of the moon (2020) · cites this paper as [3]

    In “Metabolic Regulation Is a Component of the Cell Growth Machinery” (page unavailable), the paper predicts increased mitochondrial ROS in cells with excess nutrient uptake that have *not* converted to aerobic glycolysis—the opposite of the claim that aerobic glycolysis generates high ROS. It also describes oncogenes as driving glucose uptake, not ROS as increasing oncogene activity. The section does link ROS to DNA damage, but not through the claimed pathway. (LLM, conf=0.88)

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

  • Metabolic phenotype of immortalized cell lines may diverge from native metabolic profile of their tissue of origin.

    “As a result, the metabolic phenotype of immortalized cell lines may diverge from the native metabolic profile of their tissue of origin (Vander Heiden et al. 2009;Liberti and Locasale 2016).”

    From Primary cell cultures versus immortalized cell lines: critical comparative insights into biological fidelity and translational applications (2026) · cites this paper as Vander Heiden et al. 2009

    The section “Proliferating Mammalian Cells Exhibit Anabolic Metabolism” contrasts the metabolism of most cancer cells with that of differentiated tissues. The section “What Triggers the Switch from Oxidative Phosphorylation to Aerobic Glycolysis?” likewise describes metabolism changing with proliferation or tissue-specific needs. Neither passage specifically addresses immortalized cell lines or compares them with their tissues of origin. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Augmentation of aerobic glycolysis could aid in the mitigation of reactive oxygen species and facilitate the production of a greater quantity of amino acids to support protein synthesis in osteoblasts.

    “Moreover, the augmentation of aerobic glycolysis could aid in the mitigation of reactive oxygen species and additionally facilitate the production of a greater quantity of amino acids to support protein synthesis in osteoblasts [58].”

    From Mesenchymal stromal cells in bone marrow niche of patients with multiple myeloma: a double-edged sword (2025) · cites this paper as [58]

    In “Metabolic Regulation Is a Component of the Cell Growth Machinery” (page not available), the paper predicts greater ROS production in cells that have not switched to aerobic glycolysis. In “Crunching the Numbers” (page not available), it explains how glycolytic intermediates can supply precursors for amino acid synthesis. These passages discuss proliferating cells generally, not osteoblasts, and do not establish increased amino acid production or protein synthesis in osteoblasts. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • The ATP necessary for fungal cell growth and function is synthesized mainly through oxidative phosphorylation (OXPHOS), with the key enzyme being F1Fo-ATP synthase.

    “The ATP that is necessary for fungal cell growth and function is synthesized mainly through oxidative phosphorylation (OXPHOS), with the key enzyme being F1Fo-ATP synthase4.”

    From The δ subunit of F1Fo-ATP synthase is required for pathogenicity of Candida albicans (2021) · cites this paper as [4]

    The section “Why Do Proliferating Cells Switch to a Less Efficient Metabolism?” says oxidative phosphorylation can produce ATP, but also says many unicellular organisms proliferate using fermentation. The paper does not establish that fungal cells obtain most of their ATP through OXPHOS or identify F1Fo-ATP synthase as the key enzyme. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • PI3K signaling may be central to linking common genetic perturbations of cancer, such as RTK mutations and PTEN loss, with altered metabolic processes, including the lipogenic phenotype common to many cancers, including GBM.

    “PI3K signaling may be central to linking the common genetic perturbations of cancer, such as RTK mutations and PTEN loss, with altered metabolic processes, including the “lipogenic phenotype” common to many cancers, including GBM (13, 14, 17, 20).”

    From An LXR Agonist Promotes Glioblastoma Cell Death through Inhibition of an EGFR/AKT/SREBP-1/LDLR–Dependent Pathway (2011) · cites this paper as [17]

    “Metabolic Regulation Is a Component of the Cell Growth Machinery” links PI3K signaling to growth control and glucose metabolism. “Crunching the Numbers–What Are the Metabolic Needs of Proliferating Cells?” describes fatty-acid synthesis, but our copy does not link PI3K to a lipogenic phenotype or establish the claimed connection through RTK mutations and PTEN loss, including in GBM. The indexed passages provide no page numbers. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

Cites

Flagged first, then by citations

Research works printed but not linked: 2

  1. Warburg O., Posener K., Negelein E., Biochem. Z. 152, 319 (1924).
  2. Sonveaux P., et al.., J. Clin. Invest. 118, 3930 (2008).Medline

Cited by

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Related

Authors
Vander Heiden, M. G., Cantley, L. C., & Thompson, C. B.
Affiliations
  • Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
  • Harvard University (US)
  • Abramson Cancer Center (US)
Corresponding author
  • Cantley, Lewis C.
  • Thompson, Craig B.
ORCID
Venue
Science
Publisher
American Association for the Advancement of Science (AAAS)
Published
2009-05-22
Volume
324
Issue
5930
Pages
1029-1033
ISSN
  • 0036-8075 (ISSN-L)
  • 1095-9203
DOI
10.1126/science.1160809
PMC
PMC2849637
OpenAlex
W2097259163
Semantic Scholar
5a3b09333eb2968904933e726dc29625e10eb188
Cited by
16,197
References
47
Citations by year
2026: 969 · 2025: 1224 · 2024: 1225 · 2023: 1156 · 2022: 1351 · 2021: 1439 · 2020: 1276 · 2019: 1065 · 2018: 1028 · 2017: 1027 · 2016: 921 · 2015: 823 · 2014: 727 · 2013: 665 · 2012: 535
FWCI
27.05
Type
journal article
Language
en
Open access
Locations
  • Science (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Cancer Institute (R01CA092660, R01CA105463, T32CA009172)
  • National Institute of General Medical Sciences (R01GM056203)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer and biochemical research
Keywords
Warburg effect, aerobic glycolysis, cancer metabolism, cell proliferation, mitochondrial oxidative phosphorylation, ATP production, signaling pathways, cancer-associated mutations, growth regulation
MeSH terms
Adenosine Triphosphate, Aerobiosis, Amino Acids, Animals, Glucose, Glycolysis, Humans, Lipids, Mutation, Neoplasms, Nucleotides, Oxidative Phosphorylation, Signal Transduction, Cell Proliferation, Metabolic Networks and Pathways

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