The significant role of amino acid metabolic reprogramming in cancer

Abstract

Amino acid metabolism plays a pivotal role in tumor microenvironment, influencing various aspects of cancer progression. The metabolic reprogramming of amino acids in tumor cells is intricately linked to protein synthesis, nucleotide synthesis, modulation of signaling pathways, regulation of tumor cell metabolism, maintenance of oxidative stress homeostasis, and epigenetic modifications. Furthermore, the dysregulation of amino acid metabolism also impacts tumor microenvironment and tumor immunity. Amino acids can act as signaling molecules that modulate immune cell function and immune tolerance within the tumor microenvironment, reshaping the anti-tumor immune response and promoting immune evasion by cancer cells. Moreover, amino acid metabolism can influence the behavior of stromal cells, such as cancer-associated fibroblasts, regulate ECM remodeling and promote angiogenesis, thereby facilitating tumor growth and metastasis. Understanding the intricate interplay between amino acid metabolism and the tumor microenvironment is of crucial significance. Expanding our knowledge of the multifaceted roles of amino acid metabolism in tumor microenvironment holds significant promise for the development of more effective cancer therapies aimed at disrupting the metabolic dependencies of cancer cells and modulating the tumor microenvironment to enhance anti-tumor immune responses and inhibit tumor progression.

Keywords: Amino acid metabolism; Angiogenesis; Epigenetic regulation; Immune tolerance; Redox; Tumor microenvironment.

Fig. 1

Amino acid metabolism maintains the redox homeostasis in tumor cells. The intracellular maintenance of redox balance primarily relies on glutathione, Thioredoxin and NADPH. Cysteine and glutamate are transported into and out of tumor cells via the bidirectional transporter SLC7A11. Cysteine is intracellularly converted to cystine, while glutamine enters cells through the transporter SLC1A5 and is converted to glutamate by GLS. Furthermore, glutamate can also be converted to glutamine through GS. Both glutamate and cysteine serve as precursors for GSH synthesis. Glutamate can further be metabolized into α-KG and aspartate, generating NADPH through the TCA cycle. Moreover, the PPP pathway of glucose metabolism also contributes to NADPH production. Additionally, glutamate can be transformed into GSA and P5C, eventually leading to proline synthesis, a process that involves the interconversion of NADPH and NADP+. Within thioredoxin, cysteine participates in antioxidant activities by serving as a substrate for protein reduction, facilitated by sulfhydryl-disulfide exchange reactions with TrxR and the NADPH system. SLC7A11 Solute carrier family 7 member 11, SLC1A5 Solute carrier family 1 member 5, NADPH nicotinamide adenine dinucleotide phosphate diaphorase, GSH glutathione, GLS glutaminase, GS glutamine synthetase, GSA glutamic semialdehyde, P5C pyrroline-5-carboxylate, TCA tricarboxylic acid cycle, PPP pentose phosphate pathway. Image created with BioRender.com

Fig. 2

Amino acid metabolism regulates the epigenetic modification in tumor cells. Amino acid metabolism participates in epigenetic regulation by providing methyl groups, acetyl coenzyme A, succinyl-CoA, citrulline, β-hydroxybutyrylation and serving as modification sites. In the intricate processes of the folate and methionine cycles involving one-carbon metabolism, the conversions of serine and glycine play pivotal roles. Within the methionine cycle, homocysteine and methionine yield SAM, functioning as a methyl donor for DNA, RNA, and histone methylation. Branch-chain amino acids undergo transamination to form BCKAs, eventually leading to the conversion of α-ketoglutarate to glutamate. Glutamate further transforms into glutamine, participating in TCA cycle. The BCKAs are catalyzed by BCKDH to yield R-CoA, subsequently metabolized into acetyl-CoA. Acetyl-CoA can either be converted into citrate by CS or via ACLY to replenish the acetyl-CoA pool. Additionally, gluconeogenic amino acids can fuel the TCA cycle. Succinyl-CoA, an intermediate metabolite from branch-chain amino acid breakdown and TCA cycle, serves as a substrate for histone succinylation. Moreover, acetyl-CoA participates in ketone body-mediated modifications and the conversion of glutamate to arginine within the TCA cycle supports histone citrullination. SAM S-adenosylmethionine, BCKAs branched-chain keto acids, ATP-citrate lyase, BCKDH branched-chain α-ketoacid dehydrogenase complex, CS citrate synthase. Image created with BioRender.com

Fig. 3

The influence of amino acids in regulating the activity and function of immune cells in microenvironment. Lymphoid immune cells encompass T cells, regulatory T cells, NK cells, and B cells, while myeloid immune cells consist of macrophages, neutrophils, dendritic cells, and MDSCs. Various studies have indicated that amino acids such as arginine, cysteine, glycine, glutamine, tryptophan, arginine, serine, BCAAs, aspartate, and selenium-containing amino acids play regulatory roles in the activation, proliferation, and function of immune cells within the tumor microenvironment. The red line represents the effect of amino acids on lymphocytes and the blue line represents the effect on myeloid cells. BCAAs branched-chain amino acids, MDSCs myeloid-derived suppressor cells. Image created with BioRender.com

Fig. 4

Amino acid metabolism regulates tumor angiogenesis. The metabolism of amino acids can impact not only the function of endothelial cells but also the formation and function of blood vessels. Glutamine is catalyzed by GLS to form glutamate, which can be converted to aspartate to promote endothelial cell germination. Glutamate can also be converted to P5C and proline, further facilitating ECM remodeling. Following VEGF signaling stimulation, endothelial cells exhibit increased glycine uptake, which can enhance endothelial cell migration. Glycine is also involved in GSH synthesis, inhibiting vascular tone, blood pressure, and oxidative stress mediated by NO. Arginine, through the synthesis of proline, polyamines, and NO, plays a regulatory role in angiogenesis. The serine synthesis pathway dependent on PHGDH can promote antihypertensive effects, regulate oxidative stress, and resist endothelial cell apoptosis. Additionally, tryptophan metabolism in MDSCs generates kynurenine via IDO-1, regulating the balance between IFNγ and IL6. While IL6 promotes angiogenesis, IFNγ exerts the opposite effect. GSH glutathione, GLS glutaminase, ECM extracellular matrix, VEGF vascular Endothelial Growth Factor, PHGDH phosphoglycerate dehydrogenase. Image created with BioRender.com