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. 2015 Aug;11(4):787-796.
doi: 10.1007/s11306-014-0760-9.

The Warburg effect: a balance of flux analysis

B Vaitheesvaran  1 , J Xu  2 , J Yee  3 , Lu Q-Y  4 , V L Go  4 , G G Xiao  5 , W N Lee  6
Affiliations

The Warburg effect: a balance of flux analysis

B Vaitheesvaran et al. Metabolomics. 2015 Aug.

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.

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Conflict of interest statement

Disclosure statement: The authors have no conflicts of interest to disclose.

Figures

Figure 1
Figure 1
Balance of flux equations for anaerobic glycolysis and pentose phosphate cycle showing similar lactate production but substantial difference in energy production of these processes. These equations form the basis of a balance of flux model for the glycolytic/pentose cycle compartment.
Figure 2
Figure 2
Pentose phosphate Pathways (PPP). Fig. 2A shows the PPP operating in the oxidative mode producing NADH and triose phosphates. Fig. 2B shows the PPP operating in the non-oxidative mode producing pentose phosphate. Whether PPP operates in the oxidative or the non-oxidative mode depends on relative contribution of G6PDH and transketolase/transaldolase action, substrate inputs (G6P, F6P, Triose-P (3C)), NADH/NAD ratio and the removal of F6P by the formation of F1,6 diP, and triose-P by pyruvate kinase. The rate of PPP is reflected by the concentrations of the intermediates shown in the figures F6P (6C), Pentose-P (5C), sedoheptulose-P (7C) and erythrose-P (4C). These intermediates are parts of the sugar phosphate system consisting of ketoses, aldoses and sugar alcohols. Oxidation of these compounds initiates their catabolism and conversion to amino acid precursors. Notable example is the oxidation of glycerol to pyruvate and lactate.
Figure 3
Figure 3
Tricarboxylic acid (TCA) compartment. The pyruvate compartment connects the glycolytic/pentose cycle compartment to the TCA cycle compartment shown on top of the figure. The reactions in this compartment are shown in Figures 5 and 6. The input into the TCA cycle system starts with the carboxylation of pyruvate to OAA (4C), and condensation of OAA with acetyl-CoA forming citrate (6C). Energy is released in subsequent segments of the TCA cycle. Therefore, interruption of the cycle by the loss of intermediates through anaplerosis can impair the progression of the TCA reducing the rate of oxygen consumption and ATP production. The role of anaplerosis in OXPHOS is also predicted by the balance of flux consideration on equations in Figures 4 and 2S. The TCA cycle intermediates are the precursors of a large number of biosynthesis such as fatty acids and sterols synthesis from acetyl-CoA, and synthesis of compounds such as proline, ornithine, and polyamines from α-ketoglutarate and glutamate.
Figure 4
Figure 4
Balance of flux equations for TCA cycle assuming constant levels of intermediates. Energy from reducing equivalents FADH and NADH are transferred through the electron chain transport (ECT) ultimately reacting with oxygen to generate ATP. Reactive oxygen species and heat are generated as byproducts of OXPHOS.
Figure 5
Figure 5
Anaplerotic reactions are reactions that can fill or drain intermediates from the TCA cycle. TCA cycle intermediates are shown in text-box and the anaplerotic reactions are indicated by the dotted lines. In the normal operation of the TCA cycle, the primary source of TCA cycle intermediates is from conversion of pyruvate to oxaloacetate (OAA). In cancer metabolism, a large amount of glutamate and aspartate is required for nucleic base synthesis. Input from glutamate and aspartate is often necessary to maintain a high rate of cell proliferation. Conversion of pyruvate to OAA, OAA to PEP and α-KG to succinyl-CoA are the only irreversible reactions. Interconversion of these substrates results in futile cycling and consumption of ATP.
Figure 6
Figure 6
Energy metabolism in cells comprises of a spectrum of anabolic and catabolic activities. These activities are driven by a hybrid system; one generating predominantly NADH and the other ATP. Previous tracer studies have shown cells capable of utilizing these two energy source for cell proliferation and other metabolic functions. Effective cancer treatment mostly affects the anabolic system and anaplerosis. Evidence is lacking as to the effectiveness of inhibiting OXPHOS as a cancer treatment.
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