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Amino Acids in Cancer Elizabeth L Lieu et al. Experimental & Molecular Medicine (2020) 52:15–30 https://doi.org/10.1038/s12276-020-0375-3 Experimental & Molecular Medicine REVIEW ARTICLE Open Access Amino acids in cancer Elizabeth L. Lieu1,TuNguyen1,ShawnRhyne1 and Jiyeon Kim1 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. Introduction leucine, and isoleucine) are alternative sources of organic The near century of progress1 in cancer metabolism molecules that can also fuel the TCA cycle3. continues to impact our understanding of oncology. Each Biosynthetic pathways, like bioenergetic pathways, also decade has yielded new discoveries and engendered rely on various amino acid contributors. Through acetyl- 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; additional avenues of research and approaches to therapy. CoA synthesis, lipogenesis can be mediated by catabolism Classically, cancer metabolism has focused on central of BCAAs3. Nucleotide synthesis, which can be delineated carbon metabolism, including glycolysis and the tri- into purine and pyrimidine biosynthesis, is another amino carboxylic acid cycle (the citric acid cycle, TCA cycle). acid-dependent process4. Glycine, glutamine, and aspar- However, new studies have shed light on the important tate serve as carbon and nitrogen donors for purine bio- role of amino acids in cancer metabolism. Amino acids synthesis5. Additional sources of carbon for nucleobases also serve the essential purposes of redox balance, ener- as a form of formate include glycine, serine, and getic regulation, biosynthetic support, and homeostatic methionine, which provide one-carbon units through the – maintenance. This wide breadth of metabolic activities methionine–folate cycle6 8. has made amino acid metabolism increasingly popular in Amino acids produce derivatives that also support cancer research. cancer growth and metastatic potential. Arginine-derived While glucose is a renowned energy source for cancer polyamines alter gene expression by modulating global growth, amino acids are also important fuels supporting chromatin structure and cancer cell proliferation9. cancer development. Glutamine, for example, is largely Kynurenine produced from tryptophan induces immu- anaplerotic and relinquishes both amine groups to sup- nosuppression10,11 by binding to and activating the tran- – port the TCA cycle2. In addition to glutamine, other scription factor aryl hydrocarbon receptor (AhR)12 14. amino acids can function as opportunistic fuel sources for This impairs the ability of immune-tolerant dendritic cells cells. Branched-chain amino acids (BCAAs; valine, (DCs) and regulatory T cells to target and eliminate cancer cells11,15. Cancer cell proliferation results in the accumulation of Correspondence: Jiyeon Kim ([email protected]) reactive oxygen species, which can damage macro- 1Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL, USA molecules and ultimately lead to cell death. To counter These authors contributed equally: Elizabeth L. Lieu, Tu Nguyen, Shawn Rhyne © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a linktotheCreativeCommons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Official journal of the Korean Society for Biochemistry and Molecular Biology Lieu et al. Experimental & Molecular Medicine (2020) 52:15–30 16 this, cancer cells are reliant upon the synthesis of glu- The principal focus of this review is the specific rela- tathione from glutamate, glycine, and cysteine to mediate tionship between amino acids and cancer metabolism. – redox balance16 18. While NADPH sourced from glyco- Relevant work detailing nonessential amino acid (NEAA) lysis and the pentose phosphate pathway are commonly metabolism, transporters, and transaminase in cancer is – identified as the main contributors to redox balance, a covered in several reviews and in the cited articles2,6,41 44. significant amount of NADPH is also produced by the These in combination with recently published studies folate cycle, which is primarily driven by serine-derived supplement the discussion of the roles of amino acids, one-carbon units19. which include bioenergetic formation, biosynthetic In addition to the direct integration of amino acids and activity, and resistance to metabolic stress. This review their derivatives in metabolic reprogramming processes, also discusses the regulation of amino acid metabolism amino acids are also fundamental in mediating epigenetic in cancer, therapies that are under investigation, and regulation and posttranscriptional modification. For aspects of amino acid metabolism relevant to inhibition example, DNA and histone methylation are regulated by with a specific focus on transaminases and amino acid balanced metabolite levels in the methionine cycle, which transporters. are influenced by methionine, serine, and glycine20,21. Similarly, histone acetylation events promoting gene Amino acids as alternative fuels expression and cancer progression require acetyl-CoA, In cancer cells, glutamine is the major amino acid that which can be derived from BCAAs and lysine22. Amino serves as an anaplerosis metabolite and drives the tri- acid-derived acetyl-CoA is also relevant for protein acet- carboxylic acid (TCA) cycle to sustain mitochondrial ATP ylation that can support tumor growth23,24. production. Anaplerotic metabolism of glutamine generates Transaminases are an important class of enzymes for α-ketoglutarate (α-KG) and subsequently oxaloacetate cancer. By facilitating the interconversion of amino acids, (OAA) and fuels the TCA cycle through a series of bio- transaminases allow for the exploitation of the diverse chemical reactions termed glutaminolysis2 (Figs. 1, 4b). functions of amino acids from irregular sources. Aspartate Under glucose-deprived conditions, glutamine-derived transaminase (AST, or glutamic oxaloacetic transaminase fumarate, malate, and citrate are significantly increased45. (GOT1 and 2)) is essential for redox balance and growth in Similarly, under hypoxia or in cancer cells with mitochon- pancreatic cancer cells25. In colorectal cancer, phospho- drial dysfunctions, the direction of metabolic flow and uti- serine aminotransferase 1 (PSAT1) levels have been impli- lization of glutamine is drastically changed. In such cated in poor prognosis26. The high demand for essential conditions, α-KG from glutamine can undergo reductive amino acids (EAAs) to support cancer cell growth leads to carboxylation to generate isocitrate, which is then converted the upregulation of EAA transporters to meet these into citrate46,47. Upon glutamine deprivation, asparagine – requirements, a common feature of many cancers27 29. plays a critical role in suppressing apoptotic cell death48,49. The wide range of amino acid functions, including The positive regulator that transduces a signal from gluta- amino acid synthesis, breakdown, and transport, has mine depletion to apoptosis is citrate synthase (CS)48. provided numerous targets for the development of drugs. Under normal circumstances, CS condenses OAA from Amino acid-degrading enzymes such as arginase and glutamine with acetyl-CoA to maintain the TCA cycle asparaginase have been shown to exert antitumor effects function. Silencing CS leads to enhanced OAA diversion – in preclinical and clinical settings;30 34 however, addi- from the TCA cycle to aspartate and asparagine biosynth- tional pathways involving amino acid transport and esis, protecting cells from glutamine depletion-mediated synthesis suggest effective therapies. Transporters are apoptosis48. Exogenous asparagine completely restored cell attractive therapeutic targets given the availability of survival under glutamine-depleted conditions, whereas various transport
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