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Review
. 2021 Jul 30;12(4):1461-1480.
doi: 10.1093/advances/nmaa174.

Metabolic Strategies for Inhibiting Cancer Development

Philippe Icard  1   2   3 , Mauro Loi  4 , Zherui Wu  5   6 , Antonin Ginguay  7   8 , Hubert Lincet  9   10 , Edouard Robin  3 , Antoine Coquerel  11 , Diana Berzan  3 , Ludovic Fournel  3   6 , Marco Alifano  3   12
Affiliations
Review

Metabolic Strategies for Inhibiting Cancer Development

Philippe Icard et al. Adv Nutr. .

Abstract

The tumor microenvironment is a complex mix of cancerous and noncancerous cells (especially immune cells and fibroblasts) with distinct metabolisms. These cells interact with each other and are influenced by the metabolic disorders of the host. In this review, we discuss how metabolic pathways that sustain biosynthesis in cancer cells could be _targeted to increase the effectiveness of cancer therapies by limiting the nutrient uptake of the cell, inactivating metabolic enzymes (key regulatory ones or those linked to cell cycle progression), and inhibiting ATP production to induce cell death. Furthermore, we describe how the microenvironment could be _targeted to activate the immune response by redirecting nutrients toward cytotoxic immune cells or inhibiting the release of waste products by cancer cells that stimulate immunosuppressive cells. We also examine metabolic disorders in the host that could be _targeted to inhibit cancer development. To create future personalized therapies for _targeting each cancer tumor, novel techniques must be developed, such as new tracers for positron emission tomography/computed tomography scan and immunohistochemical markers to characterize the metabolic phenotype of cancer cells and their microenvironment. Pending personalized strategies that specifically _target all metabolic components of cancer development in a patient, simple metabolic interventions could be tested in clinical trials in combination with standard cancer therapies, such as short cycles of fasting or the administration of sodium citrate or weakly toxic compounds (such as curcumin, metformin, lipoic acid) that _target autophagy and biosynthetic or signaling pathways.

Keywords: body composition; drug resistance; glycolysis; immunity; metabolism; tumor microenvironment.

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Figures

FIGURE 1
FIGURE 1
Key figure summarizing the different metabolic strategies which enable inhibition of cancer development.
FIGURE 2
FIGURE 2
The metabolism of cancer cells relying on the Warburg effect. Cancer cell metabolism is supported by glycolysis, glutaminolysis, and/or FAO. Glycolysis is enhanced: PFK1 is promoted by F2,6P produced by PFKFB3. Dimeric embryonic PKM2 creates a bottleneck at the end of glycolysis promoting branched pathway activities: PPP provides R5P for nucleotide synthesis, the DHAP pathway provides G3P for triglyceride synthesis, and SGFMP sustains protein and glutathione synthesis, as well as one-carbon metabolism required for methylation processes (in particular of epigenome and genome), and for polyamine formation. The Warburg effect is related to PDH inhibition by PDK1, a process stimulated by HIF1 and AKT. Lactate produced by LDH5 is expulsed by MCT4. Due to PDH inactivation, acetyl-CoA is produced by FAO or derives from oxidation of AKGα, which enters the Krebs cycle (also named the TCA cycle). Cytosolic citrate derives from mitochondrial export or from carboxylation of AKG deriving from glutaminolysis. ACLY transforms citrate into OAA and acetyl-CoA. Acetyl-CoA sustains lipid synthesis and histone acetylation while OAA sustains aspartate synthesis or pyruvate and lactate formation. Glycolysis is green, PPP is blue, amino acid synthesis is purple, lipid and hormone pathways are orange, and the glutamine pathway is gray. ACLY, ATP citrate lyase; AKG, α-ketoglutarate; Akt, protein kinase B; DHAP, dihydroxyacetone phosphate; FA, fatty acids; FAO, fatty acid β-oxidation; F6P, fructose 6-phosphate; F1,6P, fructose-1,6-bisphosphate; F2,6BP, fructose-2,6-biphosphate; G, glucose; G6P, glucose 6-phosphate; GA3P, glyceraldehyde 3-phosphate; GLS1, glutaminase 1; GLUT1, membrane glucose transporter 1; Glycerol-3P, glycerol-3-phosphate; HIF1α, hypoxia inducible factor 1 alpha; HK, hexokinase; HMG-CoA, 3-hydroxy-3-methylglutaryl-CoA; LDH5, lactate dehydrogenase 5; MCT, monocarboxylate transporter; NADPH,H+, nicotinamide adenine dinucleotide phosphate; OAA, oxaloacetate; PDH, pyruvate dehydrogenase; PDK1, pyruvate dehydrogenase kinase 1; PEP, phosphoenolpyruvate; PFK1, phosphofructokinase 1; PFKFB3, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3; PGK1, phosphoglycerate kinase 1; PK, pyruvate kinase; PKM2, embryonic pyruvate kinase; PPP, pentose phosphate pathway; R5P, ribose 5-phosphate; SGFMP, serine-glycine-folate-methionine pathway; TCA, tricarboxylic acid; TPI, triosephosphate isomerase; 2-PG, 2 phosphoglycerate; 3-PG, 3 phosphoglycerate; 1,3-BPG, 1,3-bisphosphogylcerate.
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