The Warburg Effect 97 Years after Its Discovery

Abstract

The deregulation of the oxidative metabolism in cancer, as shown by the increased aerobic glycolysis and impaired oxidative phosphorylation (Warburg effect), is coordinated by genetic changes leading to the activation of oncogenes and the loss of oncosuppressor genes. The understanding of the metabolic deregulation of cancer cells is necessary to prevent and cure cancer. In this review, we illustrate and comment the principal metabolic and molecular variations of cancer cells, involved in their anomalous behavior, that include modifications of oxidative metabolism, the activation of oncogenes that promote glycolysis and a decrease of oxygen consumption in cancer cells, the genetic susceptibility to cancer, the molecular correlations involved in the metabolic deregulation in cancer, the defective cancer mitochondria, the relationships between the Warburg effect and tumor therapy, and recent studies that reevaluate the Warburg effect. Taken together, these observations indicate that the Warburg effect is an epiphenomenon of the transformation process essential for the development of malignancy.

Keywords: Warburg effect; glycolysis; oncogenes; oxidative metabolism; tumor therapy.

Figure 1

Respiratory control (A) and oxidative phosphorylation (B) of the mitochondria isolated from hepatocarcinoma ascites AH130. ACR, acceptor control ratio. C, cells, M, mitochondria.

Figure 2

Reciprocal regulation between mitochondria and glycolytic pathway. Abbreviations: ANT, adenosin nucleotide transporter; PC, Pi carrier; VDAC, voltage-dependent anion channel. Substrates: DHA-P, dihydroxyacetone phosphate; F6P, fructose-6-phosphate; FBP, fructose-1,6-biphosphate; G6P, glucose-6-phosphate; 2dP-GLY, 2-diphosphoglycerate; 2PG, 2-phosphoglycerate; 3PG, 3-phosphoglycerate; PEP, phosphoenolpyruvate. Enzymes: GA-3-PD, glyceraldehyde-3-phosphate dehydrogenase; LDH, lactate dehydrogenase; PDH, pyruvate dehydrogenase; PGK, phosphoglycerate kinase; PGM, phosphoglycerate mutase; PKM2, pyruvate kinase M2; TPI, triose-phosphate isomerase. Dotted double arrows indicate competition.

Figure 3

Glucose metabolism. Substrates: DHA-P, dihydroxyacetone phosphate; F6P, fructose-6-phosphate; FBP, fructose-1,6-biphosphate; G-1-P, glucose-1-phosphate; 2dP-GLY, 2-diphosphoglycerate; OAA, oxaloacetate; αKG, alpha-ketoglutarate; 2PG, 2-phosphoglycerate; 3PG, 3-phosphoglycerate; P-enolpyruvate, phosphoenolpyruvate. Enzymes: FBPase, fructosebiphosphatase; GA-3 PD, glyceraldehyde-3-phosphate dehydrogenase; GPI, glucose-phosphate isomerase; LDH, lactate dehydrogenase; PDH, pyruvate dehydrogenase; PGK, phosphoglycerate kinase; PGM, phosphoglycerate mutase; PKM2, (pyuvate kinase M2; PYRCX, pyruvate carboxylase; TPI, triose-phosphate isomerase. Genes are shown in the yellow rectangles. Blue arrows: activation; red blunt arrow: inhibition.

Figure 4

Effects of the lactic acid export of cells outside. Explanations in the text.

Figure 5

Modifications of dimeric and tetrameric PKM2 and nuclear effects of the different forms. Explanations in the text.

Figure 6

Reciprocal regulation of glycolysis and pentose phosphate pathway. Explanations in the text.

Figure 7

Role of glutamine in tumor metabolism and the support of HIF-dependent hypoxic response. Abbreviations: ACLY, ATP-dependent citrate lyase; ACC, Acetyl-CoA carboxylase; ALDH18A1, Aldehyde dehydrogenase 18 family, member a1; FASN, Fatty acids synthetase; P5C, proline-carboxylate; PRODH2, Hydroxyproline dehydrogenase; SCD, stearoyl CoA desaturase; SLC1A5, glutamine transporter.

Figure 8

NAD synthesis. Substrates: NA, nicotinic acid; NAD, Nicotinamide adenine dinucleotide; NAAD, nicotinic acid adenine dinucleotide; NAM, nicotinamide; NAMN, nicotinic acid mononucleotide; NMN, nicotinamide mononucleotide; PRFPP, 5-phosphoribose-1-pyrophosphate. Enzymes: NADS1, NAD synthetase; NAMPT, nicotinamide phosphoribosyltransferase; NMNAT, nicotinamide mononucleotide adenylyltransferase; NAPRT, nicotinic acid phosphoribosyltransferase.

Figure 9

Aerobic glycolysis in hepatocellular carcinomas with different levels of differentiation.