Targeting the glutamine-arginine-proline metabolism axis in cancer

Abstract

Metabolic abnormalities are an important feature of tumours. The glutamine-arginine-proline axis is an important node of cancer metabolism and plays a major role in amino acid metabolism. This axis also acts as a scaffold for the synthesis of other nonessential amino acids and essential metabolites. In this paper, we briefly review (1) the glutamine addiction exhibited by tumour cells with accelerated glutamine transport and metabolism; (2) the methods regulating extracellular glutamine entry, intracellular glutamine synthesis and the fate of intracellular glutamine; (3) the glutamine, proline and arginine metabolic pathways and their interaction; and (4) the research progress in tumour therapy targeting the glutamine-arginine-proline metabolic system, with a focus on summarising the therapeutic research progress of strategies targeting of one of the key enzymes of this metabolic system, P5CS (ALDH18A1). This review provides a new basis for treatments targeting the metabolic characteristics of tumours.

Keywords: ALDH18A1; Glutamine; cancer; metabolism; proline.

Figure 1.

Functions of P5CS in different tissues. Mammalian P5CS undergoes alternative splicing to produce two isoforms. P5CS.short (the short isoform), which is inhibited by ornithine and converts glutamine to P5C, has high activity in the intestine. P5CS.long (the long isoform) has a broad tissue distribution, is insensitive to ornithine inhibition, and is involved in proline biosynthesis. This pathway is regulated by proline inhibition of P5CR. Abbreviations: P5C: pyrroline-5-carboxylic acid; P5CS: pyrroline-5-carboxylic acid synthase; P5CR: pyrroline-5-carboxylic acid reductase. The elements of the figure were downloaded for free from BioRender.com and then combined and drawn by the author.

Figure 2.

Interactions among glutamine-arginine-proline metabolism. P5C acts as a carbon skeleton and is an important intermediate metabolite in the interconversion of glutamine, arginine and proline. GSA and P5C are tautomers. Their interconversions are spontaneous. The sources of glutamine are shown on the top left, and the source of proline is shown on the top right. Glutamine enters the cell via SLC1A5 and can be converted to glutamate by glutaminase. P5CS is the first enzyme that converts glutamate to proline. Proline is converted to arginine via the P5C intermediate. Arginase then catalyses the forward conversion of arginine to ornithine, and OAT reversibly converts ornithine to P5C. Activation of the oncogenes K-Ras and MYC further increases SLC1A5 expression. MYC increases the gene expression of P5CS and PYCR, thereby increasing glutamine and proline uptake and metabolism rates. Abbreviations: ECM: extracellular matrix; GSA: gamma-glutamyl semialdehyde; P5C: pyrroline 5-carboxylate; GLU: glutamate; GLN: glutamine; PRO: proline; GLS: glutaminase; P5CS: P5C synthase; P5CDH: P5C dehydrogenase; P5CR: P5C reductase; PRODH: proline dehydrogenase; OAT: ornithine-δ-transaminase; ORN: ornithine; PA: polyamine; OTC: ornithine transcarbamylase; ASS: argininosuccinate synthase; ASL: argininosuccinate lyase; ARG: arginine; ARGases: arginase enzymes, including ARG1 and ARG2. The elements of the figure were downloaded for free from BioRender.com and then combined and drawn by the author.

Figure 3.

CMap analysis was performed to identify potential therapeutic drugs that target glutamine, arginine and proline metabolism. (A) CMap analysis was performed to identify potential therapeutic drugs that target glutamine metabolism. (B) CMap analysis was performed to identify potential therapeutic drugs that target arginine metabolism. (C) CMap analysis was performed to identify potential therapeutic drugs that target proline metabolism. Potential therapeutic drugs were analysed using Connectivity Map (https://clue.io).

Figure 4.

Crystal structure of human P5CS. (A) Crystal structure of human P5CS (PDB ID 2H5G) at amino acid positions 362–795 from the PDB database. (B) Predicted crystal structure of human P5CS (AF-P54886-F1) at amino acid positions 1–795 from the AlphaFold protein structure database. The crystal structure of human P5CS is available for free consultation and download on the Uniprot online platform (https://www.uniprot.org) .

Figure 5.

ALDH18A1 mRNA expression in patients with various types of cancer. (A) ALDH18A1 mRNA expression data are expressed as normalised transcript per million (nTPM) values in 1206 cancer cell lines from the Human Protein Atlas (HPA) database. The data are based on HPA version 23.0 and Ensembl version 109. (B) Transcript expression of ALDH18A1 in clinical tumour samples and normal tissues in the GEPIA database. The red box plots show tumour expression, while the grey colours represent normal tissues. ALDH18A1 mRNA expression was analysed using the free public databases Human Protein Atlas (HPA, http://www.proteinatlas.org) and Gene Expression Profiling Interactive Analysis (GEPIA, http://gepia.cancer-pku.cn/).