Amino acids in cancer

Abstract

Over 90 years ago, Otto Warburg's seminal discovery of aerobic glycolysis established metabolic reprogramming as one of the first distinguishing characteristics of cancer¹. The field of cancer metabolism subsequently revealed additional metabolic alterations in cancer by focusing on central carbon metabolism, including the citric acid cycle and pentose phosphate pathway. Recent reports have, however, uncovered substantial non-carbon metabolism contributions to cancer cell viability and growth. Amino acids, nutrients vital to the survival of all cell types, experience reprogrammed metabolism in cancer. This review outlines the diverse roles of amino acids within the tumor and in the tumor microenvironment. Beyond their role in biosynthesis, they serve as energy sources and help maintain redox balance. In addition, amino acid derivatives contribute to epigenetic regulation and immune responses linked to tumorigenesis and metastasis. Furthermore, in discussing the transporters and transaminases that mediate amino acid uptake and synthesis, we identify potential metabolic liabilities as targets for therapeutic intervention.

Fig. 1. Amino acids in metabolic pathways.

Metabolic reprogramming is a staple of cancer cell growth and proliferation. Both essential and nonessential amino acids (EAAs and NEAAs) support altered metabolism by serving as energy sources, biosynthetic molecules, and mediators of redox balance. Amino acids produce metabolic intermediates, such as acetyl-CoA, that sustain energy synthesis through the citric acid cycle. Amino acids also provide building blocks for nucleotide synthesis and lipogenesis that are critical to a cell’s ability to grow and develop. To circumvent the effects of oxidative stress, amino acids can regulate redox balance through their production of glutathione. Furthermore, EAA catabolism contributes to the generation of NEAAs through chemical reactions, including those mediated by transaminases. Amino acids are in green, and other metabolites are in red. Orange represents transporters. Yellow boxes signify enzymes. SHMT1 serine hydroxymethyltransferase, cytosolic, BCAT branched-chain amino acid transaminase, mitochondrial, BCAA branched-chain amino acid (valine, leucine, isoleucine), BCKA branched-chain ketoacid, GOT1 aspartate transaminase, cytosolic (AST), GLS glutaminase, GS glutamine synthetase (cytosolic and mitochondrial), ASNS asparagine synthetase, PRODH pyrroline-5-carboxylate dehydrogenase, PYCR pyrroline-5-carboxylate reductase, P5C pyrroline-5-carboxylate, GSH glutathione, Gly glycine, Ser serine, Met methionine, Met cycle methionine cycle, Gln glutamine, Cys cysteine, Glu glutamate, Asp aspartate, Pro proline, Asn asparagine, Arg arginine, PRPP phosphoribosyl pyrophosphate, acetyl-coA acetyl-coenzyme A, α-KG alpha-ketoglutaric acid, OAA oxaloacetic acid, LAT1 large-neutral amino acid transporter 1, SLC25A44 solute carrier family 25 member 44, GLUT glucose transporter, TCA cycle the tricarboxylic acid (also known as the citric acid cycle).

Fig. 2. Biochemical reactions in amino acid metabolism.

a Reverse-transsulfuration pathway: Cysteine can be produced from methionine through the reverse-transsulfuration pathway. This pathway is a combination of the methionine cycle and transsulfuration pathway. Homocysteine, the intermediate of the first step in the transsulfuration pathway, is generated from the methionine cycle. Serine condenses with homocysteine, producing cystathionine. Cystathionine is then converted to cysteine and alpha-ketobutyrate by CGL. Key enzymes are in red circle. THF tetrahydrofolate, CBS cystathionine β-synthase, SAM S-adenosylmethionine, CGL cystathionine γ-lyase. b Polyamine synthesis: Polyamines (putrescine, spermine, and spermidine) are synthesized from the amino acid arginine, and are converted from one to another (in the order of putrescine to spermidine to spermine). SAM, as the precursor of dcSAM, is the major donor for constructing polyamine structures. Key enzymes are in red circle. ODC ornithine decarboxylase, AMD S-adenosylmethionine decarboxylase, SAM S-adenosylmethionine, dcSAM decarboxylated S-adenosylmethionine. c Nitrogen and carbon source for nucleic acids: Aspartate, glycine, and glutamine provide nitrogen, and glycine and one-carbon units from the folate cycle (as a form of formate) provide carbon for purines. Glycine is formate’s indirect precursor through one-carbon metabolism, providing formate for biochemical reactions in purine biosynthesis. Aspartate and glutamine are the main amino acids involved in pyrimidine synthesis. Carbon (C) is in yellow, and nitrogen (N) is in green. d GSH and NADPH as antioxidants: Reactive oxygen species (ROS) bind and damage cellular macromolecules. The oxidation of NADPH and GSH allows ROS to be reduced to an inactive state. GSH reduces hydrogen peroxide to water and becomes oxidized to GSSG by GPX. Oxidized glutathione (GSSG) is then reduced back to GSH by GR in the presence of NADPH. Enzymes are shown in red circles. GPX glutathione peroxidase, GR glutathione reductase, GSH reduced glutathione, GSSG oxidized glutathione, NADPH reduced nicotinamide adenine dinucleotide phosphate, NADP+ oxidized nicotinamide adenine dinucleotide phosphate. e Amidation reaction for asparagine synthesis: Asparagine is synthesized by an amidotransferase reaction, catalyzed by asparagine synthetase (ASNS). The conserved amide group nitrogen is in a red box, while the enzyme is in a red circle.

Fig. 3. Amino acids contribute to epigenetic and protein regulation and immunosuppression.

a Amino acids provide metabolic intermediates for epigenetic regulation. One-carbon units from the methionine (shown here) and folate cycle serve as a methyl donor for DNA and histone methyltransferases, while acetyl-CoA from BCAAs and leucine can be utilized for histone acetylation. b Amino acid-derived acetyl-CoA is also involved in protein acetylation modification; a thrombopoietin (TPO)-responsive homodimeric receptor, CD110, activates lysine catabolism, which generates acetyl-CoA for LRP6 (a Wnt signaling protein) acetylation and promotes the self-renewal of tumor-initiating cells of colorectal cancer. c Elevated kynurenine (Kyn) levels originating from tryptophan via the enzymes tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO) have been shown in several cancers, including Hodgkin lymphoma, lung cancer, and ovarian cancer. Kynurenine promotes tumor cell survival by both inducing T-cell death and inducing immune tolerance in dendritic cells (DCs). Methylation and acetylation are represented by red Me and blue Ac circles, respectively. Histone methylation and acetylation are represented by curved lines. DNA methylation is represented by a straight line. Amino acids are in green, and other metabolites are in red. Orange represents receptors. Yellow boxes signify proteins. SAM S-adenosylmethionine, SAH S-adenosyl homocysteine, Met methionine, Thr threonine, BCAAs branched-chain amino acids, Leu leucine, Lys lysine, Acetyl-CoA acetyl-coenzyme A, Trp tryptophan, Kyn kynurenine, IFN-γ interferon gamma, mTORC1 mammalian target of rapamycin complex 1, TDH threonine dehydrogenase, EP300 histone acetyltransferase p300, HAT histone acetyltransferase, CD110 myeloproliferative leukemia protein (thrombopoietin receptor), TPO thrombopoietin, IDO indoleamine 2,3-dioxygenase, TDO tryptophan 2,3-dioxygenase, CTLA-4 cytotoxic T-lymphocyte-associated protein 4, T_R cell, regulatory T cell.

Fig. 4. Amino acid transporters and transaminases.

a, b Cells can either import amino acids from the extracellular environment or synthesize them inside the cell. Amino acid transporters are required to transfer them across the plasma membrane (shown in a), and transaminases are required to generate amino acids from sugar precursors and nitrogen from other amino acids (shown in b). Amino acid transporters and transaminases contribute to metabolic reprogramming in cancer through manipulation of the amino acid pool inside and outside cancer cells. Their impact on the tumor microenvironment is associated with tumor aggressiveness; some induce tumor cell growth and expansion through activation of signaling pathways (e.g., mTORC1 activation) or inactivation of tumor suppressors, while others result in apoptotic cell death. Amino acids are in green, and other metabolites are in red. Bright red represents transporters. Yellow boxes signify enzymes. The relative sizes of Lys and Arg represent the tendency to be transferred across CAT1 in a cancer setting. SLC6A14 solute carrier family 6 member 14, LAT1 large-neutral amino acid transporter 1, ASCT2 alanine, serine, cysteine-preferring transporter 2, xCT/CD98hc (4FC2) cystine/glutamate heterodimeric antiporter, CAT2B cationic amino acid transporter 2B, CAT1 cationic amino acid transporter 1, GLS glutaminase, GS glutamine synthetase, PSAT1 phosphoserine aminotransferase 1, AST aspartate aminotransferase, also known as glutamic oxaloacetic transaminase (GOT). GOT1 is in the cytosol and GOT2 in mitochondria, ASNS asparagine synthetase, ALT alanine aminotransferase, EAA essential amino acid, Na⁺, sodium ion, Cl⁻ chloride ion, Gln glutamine, Leu leucine, AA amino acid, Gly glycine, Glu glutamic acid, Cys cysteine, Cys cystine, Lys, lysine, NH₄⁺ ammonium ion, Asn asparagine, Ala alanine, Asp aspartic acid, Ser serine, PHP 3-phosphohydroxypyruvate, α-KG alpha-ketoglutarate, e⁻ electron, NADPH reduced nicotinamide adenine dinucleotide phosphate, NAD⁺ oxidized NADPH, OAA oxaloacetate.