Metabolic Intermediates in Tumorigenesis and Progression

Abstract

Traditional antitumor drugs inhibit the proliferation and metastasis of tumour cells by restraining the replication and expression of DNA. These drugs are usually highly cytotoxic. They kill tumour cells while also cause damage to normal cells at the same time, especially the hematopoietic cells that divide vigorously. Patients are exposed to other serious situations such as a severe infection caused by a decrease in the number of white blood cells. Energy metabolism is an essential process for the survival of all cells, but differs greatly between normal cells and tumour cells in metabolic pathways and metabolic intermediates. Whether this difference could be used as new therapeutic target while reducing damage to normal tissues is the topic of this paper. In this paper, we introduce five major metabolic intermediates in detail, including acetyl-CoA, SAM, FAD, NAD⁺ and THF. Their contents and functions in tumour cells and normal cells are significantly different. And the possible regulatory mechanisms that lead to these differences are proposed carefully. It is hoped that the key enzymes in these regulatory pathways could be used as new targets for tumour therapy.

Keywords: FAD; NAD+; SAM; THF; acetyl-CoA; cancer.

Figure 1

Synthesis and function of S-adenosyl-L-methionine. In the cytoplasm, MAT catalyses the synthesis of SAM from methionine, with ATP as an energy donor. SAM then participates in transsulfuration, transmethylation, decarboxylation and aminopropylation to produce cysteine, SAH and polyamine, respectively. In the nucleus, SAM participates in the methylation reaction of histone proteins and DNA, which is catalysed by KMTs/PRMTs and DNMTs, respectively, and generates SAH as a by-product. SAM downregulates the ERK1/2 and Stat3 pathways to profoundly slow cell cycle progression. SAM upregulates cell-cycle inhibitors, including p53 and p21, and decreases cyclin A and cyclin E protein levels to arrest the cell cycle. SAM increases the ratio of pro-apoptotic Bax/Bcl-2 and activates caspase-3 and PARP cleavage to induce apoptosis.

Figure 2

Synthesis and function of NAD⁺ in the cytoplasm and nucleus. In the de novo synthesis pathways, NAD⁺ is synthesized from dietary L-tryptophan (Trp). Trp is converted to quinolinic acid through several reactions. Quinolinic acid is then transformed into NAMN and NAAD; these reactions are catalysed by QPRT and NMNAT, respectively. In the salvage pathway, nicotinamide riboside (NR) or nicotinamide (NAM) is used to produce NAMN and NMN, which are then converted to NAD⁺. Cellular NAD⁺ levels are an energy level sensor, and low levels of NAD⁺ subsequently induce cell death. NAD⁺ functions as a cofactor of SIRT and PARP. As the cofactor of SIRT, NAD⁺ participates in protein deacetylation to regulate the gene expression and production of second messengers. As the cofactor of PARP, NAD⁺ participates in the transfer of ADP-ribose subunits from NAD⁺ to target proteins to regulate processes such as DNA repair, gene expression, cell survival and cell cycle progression, chromatin remodelling, genomic stability and RNA expression.

Figure 3

Synthesis, metabolic pathways and function of acetyl-CoA. Acetyl-CoA is predominantly generated in the mitochondrial matrix through glycolysis, fatty acid oxidation and catabolism of branched-chain amino acids (BCAAs), such as valine, leucine and isoleucine. Acetyl-CoA can then be transported from the mitochondria using the “citrate-malate-pyruvate shuttle” to create oxaloacetate and cytoplasm acetyl-CoA. Acetyl-CoA can be generated from the reductive carboxylation of glutamine. In addition, acetate can be used to produce cytoplasmic acetyl-CoA catalysed by acyl-CoA synthetase short-chain family member 2 (ACSS2) in an ATP-dependent manner. Synthesized acetyl-CoA is widely used as a precursor for the biosynthesis of numerous metabolites, such as fatty acids, steroids and some specific amino acids, which include glutamate, proline, and arginine. Reducing the conversion of mitochondrial-derived citrate to acetyl-CoA downregulates lipogenesis. This process also decreases cell proliferation, which is stimulated by cytokines and regulated by the PI3K/Akt signalling pathway. Citrate-derived acetyl-CoA functions as an acetyl donor for protein acetylation. In the cytoplasm, acetylation can activate the function of proteins, resulting in a series of biological activities. In the nucleus, the acetylation of the histone tail neutralizes the charge of the histone, weakens the interaction between histones and DNA, and relaxes the chromatin structure, thus facilitating transcription.

Figure 4

Synthesis and function of THF. THF is reduced from DHF by dihydrofolate reductase (DHFR) and requires NADPH as a co-factor. SHMT converts 5,10-methylene-THF into THF and simultaneously generates serine; glycine is used as the substrate. In the nucleus, 5,10-methylene-THF is converted into DHF by TYMS. In addition, methylenetetrahydrofolate dehydrogenase (MTHFD) reversibly catalyses the generation of 5,10-methylene-THF from 10-formyl-THF. Enzymes such as TYMS, DHFR and SHMT1/2α and synthesized THF translocate into the nucleus and function as a multienzyme complex for nuclear de novo dTMP synthesis, which is essential for DNA replication and genome stability.

Figure 5

The synthesis and function of FAD. The de novo synthesis of FAD requires riboflavin (Rf) as a precursor. Rf is converted into FAD via two consequent reactions: one reaction transfers a phosphoryl group from ATP to Rf to form FMN and is catalysed by riboflavin kinase; the other reaction adenylates FMN to FAD and is catalysed by FAD synthase. The synthesis of FAD can be achieved in the cytoplasm, mitochondrial matrix and nucleus. Mitochondria-derived FAD acts as a hapten and covalently attaches to specific apoproteins, the mitochondrial succinate dehydrogenase complex of the citric acid cycle, to induce a strong immune response. However, nuclear-derived FAD regulates hypoxia responses as the cofactor of lysine-specific demethylase 1 (LSD1); it can decrease the DNA expression of IL-1α, IL-1β, IL-6, and tumour necrosis factor-α via increasing H3K4me1 and H3K4me2 in exon 1. In the hypoxia response, FAD acts as the cofactor of lysine-specific demethylase 1 (LSD1). In early hypoxia, high levels of FAD activate LSD1, which inhibits the degradation of HIF-1α to promote the expression of HIF-1α target genes and induce hypoxia responses. During prolonged hypoxia, decreased cellular FAD levels attenuate the activity of LSD1, leading to the combination of RACK1 and HIF-1α and causing the degradation of HIF-1α.