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Review
. 2012 Nov;23(11):552-9.
doi: 10.1016/j.tem.2012.06.009. Epub 2012 Jul 31.

Genetically-defined metabolic reprogramming in cancer

Andrew R Mullen  1 , Ralph J DeBerardinis
Affiliations
Review

Genetically-defined metabolic reprogramming in cancer

Andrew R Mullen et al. Trends Endocrinol Metab. 2012 Nov.

Abstract

Oncogenes and tumor suppressors regulate cell metabolism. Evidence demonstrates that tumorigenic mutations in these genes tend to orchestrate metabolic activity into a platform that promotes cell survival, growth, and proliferation. Recent work has shown that some metabolic enzymes are also mutated in cancer, and that these mutations may influence malignancy directly. Thus, these enzymes seem to function as oncogenes and tumor suppressors, and would appear to be compelling targets for therapeutic intervention. Here, we review several enzymes mutated in cancer - phosphoglycerate dehydrogenase, isocitrate dehydrogenases 1 and 2, succinate dehydrogenase, and fumarate hydratase - and discuss exciting new work that has begun to pull back the curtain on how mutations in these enzymes influence tumorigenesis.

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Figures

Figure 1
Figure 1. Phosphoglycerate dehydrogenase is over-expressed in some cancers and catalyzes a growth-promoting metabolic pathway
Glycolytic cancer cells convert glucose into pyruvate, which can then be oxidized in the mitochondria or converted into lactate. Cells containing enhanced expression of the enzyme phosphoglycerate dehydrogenase (PHGDH), either as the result of genomic amplification of its gene on chromosome 1p12 or through other mechanisms, divert 3-phosphoglycerate (3-PG) away from glycolysis into the serine/glycine biosynthetic pathway (red arrows), which generates a number of important metabolic intermediates. Along this pathway, transamination of 3-phospho-hydroxypyruvate (3-POHpyr) by the enzyme phosphoserine aminotransferase-1 (PSAT1) generates α-ketoglutarate (α-KG), which can then be oxidized in the tricarboxylic acid cycle (TCA). Serine and glycine are used to produce glutathione, proteins, nucleic acids, phospholipids and sphingolipids, and other molecules required for cell growth and proliferation. Abbreviations: Ac-coA, acetyl-coA; Cit, citrate; Isocit, isocitrate; Succ, succinate; Fum, fumarate; Mal, malate; OAA, oxaloacetate; NAD, nicotine adenine dinucleotide.
Figure 2
Figure 2. Mutant IDH1/2 enzymes produce an oncometabolite with pleiotropic effects on cell signaling and epigenetics
Normal cells contain wild type IDH1 and IDH2 (gray). These enzymes catalyze the reversible conversion of isocitrate to α-ketoglutarate (α-KG), generating NADPH and CO2.. α-KG can be oxidized in the TCA or used as a cofactor by α-KG-dependent dioxygenase enzymes. Tumor cells with somatically-acquired, heterozygous active site mutations in IDH1 or IDH2 (mIDH1/2, green) display a neomorphic enzyme activity that reduces α-KG to R(−)-2-hydroxyglutarate ((R)-2HG), using NADPH as a cofactor. Due to its structural similarity to α-KG, (R)-2HG modulates the function of α-KG-dependent dioxygenases, stimulating prolyl hydroxylase activity and inhibiting a number of enzymes that regulate histone and DNA modifications. Together, these processes exert complex effects on gene expression that likely contribute to the malignancy of IDH1/2-mutant cells.
Figure 3
Figure 3. Effects of mutation of TCA cycle enzymes on metabolism and gene expression
(A) Succinate dehydrogenase (SDH) and fumarate hydratase (FH) are TCA cycle enzymes and tumor suppressors. In normal cells, succinate and fumarate are generated through oxidative metabolism of glutamine-derived α-KG (gray arrows). Subsequent metabolism around the TCA cycle generates citrate for lipid synthesis. SDH and FH deficiency interrupt this pathway, with accumulation of succinate and fumarate, respectively. FH-deficient cells redirect TCA cycle metabolism in two ways (red arrows). First, the cells shunt succinyl-CoA into a pathway of heme biosynthesis and degradation, culminating in the secretion of bilirubin. Inhibiting Heme Oxygenase-1 (HMOX1) in this pathway selectively kills cells with FH deficiency. Second, in order to produce citrate, the cells use reductive carboxylation of glutamine-derived α-KG. IDH1 and/or IDH2 participate in this reaction, and subsequent metabolism of citrate produces acetyl-CoA for fatty acid/lipid synthesis, and other TCA cycle intermediates like oxaloacetate and malate, which are normally produced downstream of FH. (B) Keap1 is an electrophile sensor. In the absence of fumarate and other electrophiles, Keap1 negatively regulates the transcription factor Nrf2, targeting it for degradation. In FH-deficient cells, cysteine residues on Keap1 are modified by fumarate-dependent succination, in which cysteine is converted to S-(2-succinyl)-cysteine. Nrf2, now active, can activate the transcription of genes involved in the antioxidant response. Abbreviations: Ac-CoA, acetyl-CoA; Succ-CoA, succinyl-CoA; OAA, oxaloacetate; HMOX1, heme oxygenase-1; IDH1/2, isocitrate dehydrogenase isoforms 1 and 2; Cys, cysteine.
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