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Review
. 2017 Dec 21:7:319.
doi: 10.3389/fonc.2017.00319. eCollection 2017.

The Central Role of Amino Acids in Cancer Redox Homeostasis: Vulnerability Points of the Cancer Redox Code

Milica Vučetić  1 , Yann Cormerais  1 , Scott K Parks  1 , Jacques Pouysségur  1   2
Affiliations
Review

The Central Role of Amino Acids in Cancer Redox Homeostasis: Vulnerability Points of the Cancer Redox Code

Milica Vučetić et al. Front Oncol. .

Abstract

A fine balance in reactive oxygen species (ROS) production and removal is of utmost importance for homeostasis of all cells and especially in highly proliferating cells that encounter increased ROS production due to enhanced metabolism. Consequently, increased production of these highly reactive molecules requires coupling with increased antioxidant defense production within cells. This coupling is observed in cancer cells that allocate significant energy reserves to maintain their intracellular redox balance. Glutathione (GSH), as a first line of defense, represents the most important, non-enzymatic antioxidant component together with the NADPH/NADP+ couple, which ensures the maintenance of the pool of reduced GSH. In this review, the central role of amino acids (AAs) in the maintenance of redox homeostasis in cancer, through GSH synthesis (cysteine, glutamate, and glycine), and nicotinamide adenine dinucleotide (phosphate) production (serine, and glutamine/glutamate) are illustrated. Special emphasis is placed on the importance of AA transporters known to be upregulated in cancers (such as system xc-light chain and alanine-serine-cysteine transporter 2) in the maintenance of AA homeostasis, and thus indirectly, the redox homeostasis of cancer cells. The role of the ROS varies (often described as a "two-edged sword") during the processes of carcinogenesis, metastasis, and cancer treatment. Therefore, the context-dependent role of specific AAs in the initiation, progression, and dissemination of cancer, as well as in the redox-dependent sensitivity/resistance of the neoplastic cells to chemotherapy are highlighted.

Keywords: NADPH/NADP+; amino acids; cancer; glutathione; redox homeostasis.

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Figures

Figure 1
Figure 1
Reactive oxygen species (ROS) can (i) promote cancer, (ii) cause growth arrest, and (iii) be cytotoxic. In normal cells, increased (endogenous or exogenous) oxidative pressure leads to adequate upregulation of cellular antioxidant defense (AOD), which prevent mutagenic events and initiation of cancer formation. However, AOD is not 100% efficient, and thus, these “challenging states” also represent well-known risk factors for cancer development. Once formed, cancer progression seems to be further stimulated by a mild pro-oxidative state due to intensified metabolism, ROS-producing foci, etc. Importantly, this state is still maintained within “redox homeostatic range” thanks to strongly upregulated AOD of cancer cells. However, due to maximized AOD, cancer cells do not support further increase in ROS levels and thus cross the threshold into the state of “oxidative stress.” If ROS level increase further (e.g., due to chemotherapy), the only way for cancer cells to prevent further damage is by decreasing ROS production via cell-cycle arrest to repair damage and prevent cell death (cytostatic effects of ROS). However, if ROS burst induces irreversible damage and/or there is not enough components required for repair systems (e.g., glutathione), cancer cells experience programmed cell death or necrosis (cytotoxic effects of ROS).
Figure 2
Figure 2
Cystine import is the rate-limiting step in glutathione biosynthesis. Cysteine can be synthesized within the cell through the trans-sulfuration pathway. However, this pathway is often insufficient in cancer cells and therefore cysteine must be imported. Different transporters are involved in the import of the reduced, cysteine (CySH), and oxidized, cystine (CySSCy) form of this semi-essential AA. The heavy-chain transporter subunit of system xc-light chain (xCT) seems to play a pivotal role in the import of CySSCy, the predominant form of cysteine in circulation. After import, CySSCy is reduced by cystine reductase and used for different purposes including GSH biosynthesis. Import of cysteine can occur via ASCT (alanine/serine/cysteine transporter) and other transporters (x).
Figure 3
Figure 3
The folate cycle is fueled by the serine synthesis pathway (SSP) and extracellular serine. SSP diverges from glycolysis at the level of 3-phosphoglycerate, which is converted into 3-phospho-hydroxipyruvate by the action of the enzyme phosphoglycerate dehydrogenase (PHDGH) and ultimately to serine following further enzymatic steps. This pathway is of great importance in cancers with mutated or overexpressed PHDGH, while serine import plays a pivotal role in maintenance of the serine cellular balance in cells with unaltered PHDGH activity. The folate cycle in the vast majority of the cells starts in mitochondria by the action of serine hydroxymethyl transferase 2 (SHMT2) which generates glycine and 5,10-methylene-tetrahydrofolate (5,10-methylene-THF). The next reaction can produce NADH or NADPH depending if methenyltetrahydrofolate dehydrogenase 2 (MTHD2) or MTHD2-like (MTHD2L) is used to convert 5,10-methylene-THF into 5,10-methenyl-THF. The same enzyme than generate one-carbon unit—10-formyl-THF, which can be used for ATP production by the enzyme (MTHD1L) or NADPH generation in the reaction catalyzed by 10-formyTHF dehydrogenase (ALDH1L2). If ATP is generated, 10-formylTHF is converted into a format that is transported into the cytosol and used by trifunctional MTHFD1 enzyme to regenerate 10-formylTHF for purine synthesis, 5,10-methylene-THF for thymidylate synthesis and homocysteine remethylation in the methionine cycle. The unidirectionality of the folate cycle seems to be provided by more oxidative mitochondrial redox state that favors use of NAD(P)+ by mitochondrial MTHD2(L).
Figure 4
Figure 4
Crossroads of NADPH-producing pathways (marked dark blue) and the pathways from which they diverge or to which they converge (marked light blue). Amino acids involved in these pathways are marked in red.
Figure 5
Figure 5
Glutamine/glutamate fates in cancer cells. Different transporters are proposed to fuel the “Glutamine addiction” of cancer cells including alanine-serine-cysteine transporter 2 (ASCT2), SNAT1/2, and L-type amino acid transporter 1 (LAT1). Once inside the cell, Gln can be use for uptake of essential AAs by LAT1. However, the vast majority of Gln is promtly deaminated to glutamate by the action of cytoplasmic or mitochondrial glutaminase (GLS1 and GLS2, respectively). If deaminated in cytosol, Glu is transferred into mitochondria, and there it is further converted into α-ketoglutarate (α-KG) to replenish the tricarboxylic acid (TCA). However, the fate of α-KG can be dual. It can follow normal TCA flow until oxaloacetate (OAA), which is then converted into asparate by aspartate dehydrogenase (GOT2) and translocated into cytoplasm or used for synthesis of asparagine and arginine (protein synthesis). However, if the α-KG is carboxylated to isocitrate and then converted into citrate, citrate is exported into the cytosol where it is used for lipid synthesis in the form of acetyl-CoA. Glutamate-derived aspartate can also be converted into OAA by cytoplasmic GOT1, commonly induced in KRAS-mutated tumors. OAA is then converted first into malate by malate dehydrogenase 1 (MDH1) and then into pyruvate by malic enzyme (ME), generating reducing power in the form of NADPH. Besides involvement in anaplerosis and NADPH production, Glu has an important role as a component of GSH, as well as a substrate for system xc-light chain (xCT) in allowing entrance of cystine into the cell.
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