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Metabolomics

, Volume 11, Issue 4, pp 787–796 | Cite as

The Warburg effect: a balance of flux analysis

  • B. Vaitheesvaran
  • J. Xu
  • J. Yee
  • Q.-Y. Lu
  • V. L. Go
  • G. G. Xiao
  • W.-N. LeeEmail author
Review Article

Abstract

Cancer metabolism is characterized by increased macromolecular syntheses through coordinated increases in energy and substrate metabolism. The observation that cancer cells produce lactate in an environment of oxygen sufficiency (aerobic glycolysis) is a central theme of cancer metabolism known as the Warburg effect. Aerobic glycolysis in cancer metabolism is accompanied by increased pentose cycle and anaplerotic activities producing energy and substrates for macromolecular synthesis. How these processes are coordinated is poorly understood. Recent advances have focused on molecular regulation of cancer metabolism by oncogenes and tumor suppressor genes which regulate numerous enzymatic steps of central glucose metabolism. In the past decade, new insights in cancer metabolism have emerged through the application of stable isotopes particularly from 13C carbon tracing. Such studies have provided new evidence for system-wide changes in cancer metabolism in response to chemotherapy. Interestingly, experiments using metabolic inhibitors on individual biochemical pathways all demonstrate similar system-wide effects on cancer metabolism as in targeted therapies. Since biochemical reactions in the Warburg effect place competing demands on available precursors, high energy phosphates and reducing equivalents, the cancer metabolic system must fulfill the condition of balance of flux (homeostasis). In this review, the functions of the pentose cycle and of the tricarboxylic acid (TCA) cycle in cancer metabolism are analyzed from the balance of flux point of view. Anticancer treatments that target molecular signaling pathways or inhibit metabolism alter the invasive or proliferative behavior of the cancer cells by their effects on the balance of flux (homeostasis) of the cancer metabolic phenotype.

Keywords

Metabolic phenotype Tracer-based metabolomics Metabolic compartments Anaplerosis Energy metabolism 

Notes

Acknowledgments

This work was supported by the National Institutes of Health (P01AT003960) and the Hirshberg Foundation for Pancreatic Cancer Research, V.B.P was supported by DK58132-01A2 and NIAID Grant U19AI091175-01.

Conflict of interest

The authors have no conflicts of interest to disclose.

Compliance with Ethical Requirements

This article does not contain any studies with human or animal subjects.

Supplementary material

11306_2014_760_MOESM1_ESM.jpg (228 kb)
Supplemental Figure S1: Glycolytic/gluconeogenic pathways and their regulation. The regulation of glycolysis is accomplished through a series of futile cycles (shown as double arrows) and reversible reactions (shown as single bidirectional arrows). The direction of flux is regulated by multiple connected pathways. In addition, it is controlled by expression and/or activation of enzymes. Since glucose is needed for numerous substrate syntheses, multiple regulatory points (double arrows) are necessary to achieve fine control of glucose flux and its directions. HEX stands for hexokinase; G6Pase, glucose-6-phosphatase; GS glycogen synthase; GP, glycogenphosphorylase; PFK, phosphofructose kinase; GAPDH, glyceraldehyde 3 phosphate dehydrogenase; PGK, phosphoglycerate kinase; PGM, phosphoglycerate mutase; ENO, enolase; PKM, pyruvate kinase isozymes M1/M2 and LDH, lactate dehydrogenase. These key control points are regulated by oncogenes and cancer suppressor genes (D’Alessandro and Zolla 2012). (JPEG 228 kb)
11306_2014_760_MOESM2_ESM.jpg (333 kb)
Supplemental Figure S2: Balance of flux equations for anaplerotic reactions. These reactions allow communication (substrate exchange) between cytosolic and mitochondrial compartments. Not included in the OAA or malate balance are equations for transamination, PEPCK, maleic reaction. Together with reactions from Figure 5, these reactions form the basis for the balance of flux model of TCA cycle compartment. (JPEG 332 kb)

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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • B. Vaitheesvaran
    • 1
  • J. Xu
    • 2
  • J. Yee
    • 3
  • Q.-Y. Lu
    • 4
  • V. L. Go
    • 4
  • G. G. Xiao
    • 5
    • 6
  • W.-N. Lee
    • 3
    • 7
    Email author
  1. 1.Department of Medicine, Diabetes Center, Stable Isotope and Metabolomics Core FacilityAlbert Einstein College of Medicine Diabetes CenterBronxUSA
  2. 2.Department of PathologyUniversity of Southern CaliforniaLos AngelesUSA
  3. 3.Division of Endocrinology and Metabolism, Department of PediatricsUniversity of CaliforniaLos AngelesUSA
  4. 4.Department of MedicineUniversity of CaliforniaLos AngelesUSA
  5. 5.Functional Genomics/Proteomics Laboratories, Creighton University Medical CenterOmahaUSA
  6. 6.School of Pharmaceutical Science and Technology at Dalian University of TechnologyDalianChina
  7. 7.LA Biomedical Research InstituteTorranceUSA

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