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Review
. 2020 Mar:33:2-22.
doi: 10.1016/j.molmet.2019.10.002. Epub 2019 Oct 18.

Metabolic functions of the tumor suppressor p53: Implications in normal physiology, metabolic disorders, and cancer

Matthieu Lacroix  1 , Romain Riscal  2 , Giuseppe Arena  3 , Laetitia Karine Linares  1 , Laurent Le Cam  4
Affiliations
Review

Metabolic functions of the tumor suppressor p53: Implications in normal physiology, metabolic disorders, and cancer

Matthieu Lacroix et al. Mol Metab. 2020 Mar.

Abstract

Background: The TP53 gene is one of the most commonly inactivated tumor suppressors in human cancers. p53 functions during cancer progression have been linked to a variety of transcriptional and non-transcriptional activities that lead to the tight control of cell proliferation, senescence, DNA repair, and cell death. However, converging evidence indicates that p53 also plays a major role in metabolism in both normal and cancer cells.

Scope of review: We provide an overview of the current knowledge on the metabolic activities of wild type (WT) p53 and highlight some of the mechanisms by which p53 contributes to whole body energy homeostasis. We will also pinpoint some evidences suggesting that deregulation of p53-associated metabolic activities leads to human pathologies beyond cancer, including obesity, diabetes, liver, and cardiovascular diseases.

Major conclusions: p53 is activated when cells are metabolically challenged but the origin, duration, and intensity of these stresses will dictate the outcome of the p53 response. p53 plays pivotal roles both upstream and downstream of several key metabolic regulators and is involved in multiple feedback-loops that ensure proper cellular homeostasis. The physiological roles of p53 in metabolism involve complex mechanisms of regulation implicating both cell autonomous effects as well as autocrine loops. However, the mechanisms by which p53 coordinates metabolism at the organismal level remain poorly understood. Perturbations of p53-regulated metabolic activities contribute to various metabolic disorders and are pivotal during cancer progression.

Keywords: Cancer; Metabolism; Normal tissue homeostasis; p53.

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Figures

Figure 1
Figure 1
WT-p53 controls multiple metabolic pathways. p53 direct target genes, and p53-interacting proteins (in green) implicated in metabolism are indicated. ABCA1 (ATP binding cassette subfamily A member 1); ABCA12 (ATP binding cassette subfamily A member 12); ACAD11 (AcylCoA Dehydrogenase Family member 11); ACER2 (Alkaline ceramidase 2); AIF (Apoptosis Inducing Factor); ALDH4 (Aldehyde dehydrogenase 4); AMPKb1 (AMP-activated kinase b1 subunit); BCL2 (B-cell lymphoma 2); Catalase; CAV (Caveolin); CEL (Carboxy Ester Lipase); CERS6 (Ceramide synthetase 6); CPT1C (Carnitine Palmitoyl transferase 1C); CYPD (Cyclophilin D); DDIT4 (DNA Damage inducible transcript 4); DHRS3 (Dehydrogenase reductase 3); dUTPase (deoxyuridine triphosphate nucleotidohydrolase), ELOVL3 (Elongation of very long chain fatty acids-like 3); FDXR (Ferredoxin Reductase); FXN (Frataxin); GAMT (Guanidinoacetate methyltransferase); GLS2 (Glutaminase 2); GLUT1 (Glucose transporter 1); GLUT4 (Glucose transporter 4); GPX1 (Glutathione Peroxidase 1); HAMP (Hepcidin); HK2 (Hexokinase II); HMGCLL1 (3-hydroxymethyl-3-methylglutaryl-CoA lyase like 1); mtSSB (Single Stranded DNA Binding protein 1); IGFBP3 (IGF-Binding protein 3); ISCU (Iron-sulfur cluster assembly enzyme); LPIN1 (Lipin 1); MCD (Malonyl-CoA Decarboxylase); MCT1 (Mono-Carboxylate transporter 1); ME1 (Malic Enzyme 1); ME2 (Malic Enzyme 2); ME3 (Malic Enzyme 3); MIEAP (Mitochondria-eating protein); mSMASE2 (Neutral sphingomyelinase); NCF2 (Neutrophilic cytosolic factor 2); NPC1L1 (Nieman-Pick C1-like 1); NOS3 (Nitric Oxide Synthase 3); OSCP (Oligomycin sensitivity-conferring protein); PANK1 (Panthotenate Kinase 1); PARK2 (Parkin); PC (Pyruvate carboxylase); PCK1 (Phosphoenolpyruvate carboxykinase 1); PFKFB4 (6-Phosphofructo-2-kinase/fructose-2,6-biphosphatase 4); PFKFB3 (6-Phosphofructo-2-kinase/fructose-2,6-biphosphatase 3); PGC1α (Peroxisome proliferator-activated receptor Gamma, Coactivator 1 alpha); PGC1β (Peroxisome proliferator-activated receptor Gamma, Coactivator 1 beta); PGAM (Muscle specific phosphoglycerate mutase); PHGDH (Phosphoglycerate Dehydrogenase); PHLDA3 (Pleckstrin homology-like domain, Family A, member 3); PLTP (Phospholipid Transfer Protein); POLG (Polymerase γ); PRODH (Proline Dehydrogenase); PTEN (Phosphatase and tensin homolog); RRAD (Ras-related associated with Diabetes); RRM2B (Ribonucleotide reductase regulatory subunit M2B); SCD1 (Stearoyl-CoA desaturase 1); SCO2 (Synthesis of cytochrome c oxidase 2); SESN1 (Sestrin 1); SESN2 (Sestrin 2); SIRT1 (Sirtuin 1); SIRT6 (Sirtuin 6); SLC2A9 (Solute carrier family 2 member 9); SLC7A3 (Solute carrier family 7 member 3); SLC7A11 (Solute carrier family 7 member 11); SOD2 (Superoxide Dismutase 2); SREBP1C (Sterol regulatory element binding transcription factor 1); TFAM (Mitochondrial Transcription Factor A); TIGAR (TP53-induced glycolysis and apoptosis regulator); TP53INP1 (Tumor Protein 53-Induced Nuclear Protein 1); TSC2 (TSC Complex subunit 2).
Figure 2
Figure 2
Overview of the known in vivo metabolic functions of WT-p53 and the consequences of their deregulation on human diseases (beyond cancer). FA, Fatty acids; FAO, Fatty Acid Oxidation; PPP, Pentose Phosphate Pathway; ROS, Reactive Oxygen Species; ATP, Adenosine Tri Phosphate.
Figure 3
Figure 3
Role of the p53 network in adaptive and stress responses. The molecular mechanisms underlying p53's implication in adaptive versus stress responses are poorly understood. In the proposed model, multiple negative feed-back loops contribute to maintain the p53 response within a range of activity that favors cell survival and ensure proper cell homeostasis. When these stresses increase in intensity and/or duration, p53 gets recruited to a subset of its target genes that leads to the elimination of damaged cells.
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