Oncogenic regulation of tumor metabolic reprogramming

Abstract

Development of malignancy is accompanied by a complete metabolic reprogramming closely related to the acquisition of most of cancer hallmarks. In fact, key oncogenic pathways converge to adapt the metabolism of carbohydrates, proteins, lipids and nucleic acids to the dynamic tumor microenvironment, conferring a selective advantage to cancer cells. Therefore, metabolic properties of tumor cells are significantly different from those of non-transformed cells. In addition, tumor metabolic reprogramming is linked to drug resistance in cancer treatment. Accordingly, metabolic adaptations are specific vulnerabilities that can be used in different therapeutic approaches for cancer therapy. In this review, we discuss the dysregulation of the main metabolic pathways that enable cell transformation and its association with oncogenic signaling pathways, focusing on the effects of c-MYC, hypoxia inducible factor 1 (HIF1), phosphoinositide-3-kinase (PI3K), and the mechanistic target of rapamycin (mTOR) on cancer cell metabolism. Elucidating these connections is of crucial importance to identify new targets and develop selective cancer treatments that improve response to therapy and overcome the emerging resistance to chemotherapeutics.

Keywords: HIF; MYC; PI3K; mTOR; metabolic reprogramming.

Figure 1. Major metabolic pathways involved in tumor metabolic reprogramming

An overview of the main catabolic and anabolic metabolic pathways supporting tumor cell growth and survival. Enzymes are shown in bold. 6PGD, 6-phosphogluconate dehydrogenase; ACLY, ATP citrate lyase; CoA, coenzyme A; GLS, glutaminase; GDH, glutamate dehydrogenase; G6PD, glucose-6-phosphate dehydrogenase; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; LDH, lactate dehydrogenase; ME1, malic enzyme 1 cytoplasmic form; ME2, malic enzyme 2 mitochondrial form; NAD⁺, nicotinamide adenine dinucleotide oxidized form; NADH, nicotinamide adenine dinucleotide reduced form; NADPH, nicotinamide adenine dinucleotide phosphate reduced form; PC, pyruvate carboxylase; PDH, pyruvate dehydrogenase; PGM, phosphoglucomutase.

Figure 2. Mitochondrial metabolism

Schematic representation of the biosynthetic and bioenergetic reactions of the TCA cycle and the oxidative phosphorylation (OXPHOS). OXPHOS is coupled to the oxidation of NADH and FADH₂, which are produced in the TCA cycle, via the electron transport chain (ETC, also known as the mitochondrial respiratory chain). The ETC comprises four complexes (I to IV) that transfer electrons generating a gradient of protons (H⁺) in the mitochondrial intermembrane space, which is used by the ATPase (complex V) to produce ATP. Reductive carboxylation of α-ketoglutarate by IDH1 and IDH2 produces citrate (dashed arrows). ACLY, ATP citrate lyase; ATP, adenosine triphosphate; CoA, coenzyme A; FADH₂, flavin adenine dinucleotide reduced form; GAC, glutaminase C; GDH, glutamate dehydrogenase; GLS1, glutaminase 1; GOT1, glutamic-oxaloacetic transaminase 1 cytoplasmic form; GOT2, glutamic-oxaloacetic transaminase 2 mitochondrial form; IDH1, isocitrate dehydrogenase cytoplasmic form; IDH2, isocitrate dehydrogenase mitochondrial form; KGA, kidney (K-type) glutaminase; LDH, lactate dehydrogenase; ME1, malic enzyme 1 cytoplasmic form ; NAD⁺, nicotinamide adenine dinucleotide oxidized form; NADH, nicotinamide adenine dinucleotide reduced form; NADP⁺, nicotinamide adenine dinucleotide phosphate oxidized form; NADPH, nicotinamide adenine dinucleotide phosphate reduced form; PC, pyruvate carboxylase; PDH, pyruvate dehydrogenase.

Figure 3. Metabolic regulation by MYC

MYC has a pivotal role in the metabolic reprogramming of tumor cells by enhancing glucose uptake and glycolysis, lactate production and export, glutamine uptake and glutaminolysis, mitochondrial biogenesis and oxidative phosphorylation, and nucleotide, folate, polyamine, proline and serine synthesis. AMD1, adenosylmethionine decarboxylase; ATP, adenosine triphosphate; CAD, carbamoyl-phosphate synthase/aspartate carbamoyltransferase/dihydroorotase; CoA, coenzyme A; CTPS1, cytidine triphosphate synthase 1; DHFR, dihydrofolate reductase; FADH₂, flavin adenine dinucleotide reduced form; GAC, glutaminase C; GART, phosphoribosylglycinamide formyltransferase, phosphoribosylglycinamide synthetase, phosphoribosylaminoimida-zole synthetase; GDH, glutamate dehydrogenase; GLS1, glutaminase 1; KGA, kidney (K-type) glutaminase; LDHA, lactate dehydrogenase A; MCT1, monocarboxylate transporter/SLC16A1 solute carrier family 16 member 1; NAD⁺, nicotinamide adenine dinucleotide oxidized form; NADH, nicotinamide adenine dinucleotide reduced form; NADP⁺, nicotinamide adenine dinucleotide phosphate oxidized form; NADPH, nicotinamide adenine dinucleotide phosphate reduced form; ODC, ornithine decarboxylase; P5CS, Δ¹-pyrroline-5-carboxylate synthetase; PHGDH, phosphoglycerate dehydrogenase; PC, pyruvate carboxylase; PDH, pyruvate dehydrogenase; PSPH, phosphoserine phosphatase; PYCR1, Δ¹-pyrroline-5-carboxylate reductase 1; SHMT1, serine hydroxymethyltransferase 1; SLC1A5, solute carrier family 1 (neutral amino acid transporter) member 5; SLC2A1, solute carrier family 2 (facilitated glucose transporter) member 1; SLC2A2, solute carrier family 2 (facilitated glucose transporter) member 2; SLC2A4, solute carrier family 2 (facilitated glucose transporter) member 4; SLC7A5, solute carrier family 7 (amino acid transporter light chain, L system) member 5; SLC19A1, solute carrier family 19 (folate transporter) member 1; SRM, spermidine synthase.

Figure 4. HIF1α regulation under normoxia

In the presence of oxygen and α-ketoglutarate, HIF1α subunits are hydroxylated on proline residues in the oxygen-dependent degradation (ODD) domain by prolyl hydroxylases (principally prolyl hydroxylase 2, PHD2). Prolyl hydroxylation is required for the binding of the von Hippel-Lindau protein (VHL), which recruits an ubiquitin ligase complex (E3) that ubiquitinates HIF1α. Ubiquitination marks HIF1α for proteasomal-mediated degradation. HIF, hypoxia inducible factor; OH, hydroxylation; Ub, ubiquitin.

Figure 5. FOXO regulation by growth factors and oxidative stress

Growth factors activate PI3K/Akt pathway, resulting in FOXO factors phosphorylation, impairment of FOXO binding activity to DNA and promotion of FOXO interaction with the chaperone protein 14-3-3, which in turn causes FOXO nuclear exclusion, cytoplasmic accumulation and ubiquitin-proteasome pathway-dependent degradation. Oxidative stress activates Jun N-terminal kinase (JNK) signaling, which phosphorylates both FOXO (at other regulatory sites than Akt) and 14-3-3 proteins, triggering the release of FOXO factors, their nuclear translocation and their transcriptional activity. Akt/PBK, protein kinase B; FOXO, forkhead box O; P, phosphate; PI3K, phosphoinositide-3-kinase.

Figure 6. Effects of PI3K and mTOR on central carbon metabolism

PI3K and mTOR signaling pathways positively regulate each other's activity, as well as glucose uptake and glycolysis, oxidative metabolism and glutaminolysis. mTOR also promotes fatty acids synthesis and cell survival and growth. ACLY, ATP citrate lyase; ATP, adenosine triphosphate; CoA, coenzyme A; FADH₂, flavin adenine dinucleotide reduced form; GAC, glutaminase C; GDH, glutamate dehydrogenase; GLS1, glutaminase 1; GOT1, glutamic-oxaloacetic transaminase 1 cytoplasmic form; GOT2, glutamic-oxaloacetic transaminase 2 mitochondrial form; IDH1, isocitrate dehydrogenase cytoplasmic form; IDH2, isocitrate dehydrogenase mitochondrial form; KGA, kidney (K-type) glutaminase; LDH, lactate dehydrogenase; ME1, malic enzyme 1 cytoplasmic form; NAD⁺, nicotinamide adenine dinucleotide oxidized form; NADH, nicotinamide adenine dinucleotide reduced form; NADP⁺, nicotinamide adenine dinucleotide phosphate oxidized form; NADPH, nicotinamide adenine dinucleotide phosphate reduced form; PC, pyruvate carboxylase; PDH, pyruvate dehydrogenase.