Regulation of nucleotide metabolism in cancers and immune disorders

• Published in: Trends in cell biology Vol. 33; no. 11; pp. 950 - 966
• Main Authors: Ali, Eunus S., Ben-Sahra, Issam
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.11.2023
• Subjects: cancer metabolism; de novo purine and pyrimidine synthesis; immune disorders; metabolic vulnerability; nucleotide signaling; signaling pathways; cancer metabolism; nucleotide signaling; signaling pathways; metabolic vulnerability; de novo purine and pyrimidine synthesis; immune disorders
• ISSN: 0962-8924; 1879-3088; 1879-3088
• DOI: 10.1016/j.tcb.2023.03.003

Activation of several signaling pathways, including RAS and mechanistic target of rapamycin complex I (mTORC1), tunes nucleotide synthesis through a variety of mechanisms.Similar to glutamine or aspartate, bicarbonate abundance is regulated and limiting for nucleotide synthesis.Targeting nucleotide metabolism may enhance the effectiveness of cancer immunotherapy by disrupting nucleotide pools and promoting immunogenicity.Carbamoyl-phosphate synthetase 2 (CPS2), aspartate transcarbamoylase (ATC), and dihydroorotase (DHO) (CAD)-induced ribosomal biogenesis in memory T cells might improve chimeric antigen receptor (CAR)-T cell therapy.De novo pyrimidine synthesis emerges as a key metabolic vulnerability in certain cancers for which drug therapies are limited. Nucleotides are the foundational elements of life. Proliferative cells acquire nutrients for energy production and the synthesis of macromolecules, including proteins, lipids, and nucleic acids. Nucleotides are continuously replenished through the activation of the nucleotide synthesis pathways. Despite the importance of nucleotides in cell physiology, there is still much to learn about how the purine and pyrimidine synthesis pathways are regulated in response to intracellular and exogenous signals. Over the past decade, evidence has emerged that several signaling pathways [Akt, mechanistic target of rapamycin complex I (mTORC1), RAS, TP53, and Hippo-Yes-associated protein (YAP) signaling] alter nucleotide synthesis activity and influence cell function. Here, we examine the mechanisms by which these signaling networks affect de novo nucleotide synthesis in mammalian cells. We also discuss how these molecular links can be targeted in diseases such as cancers and immune disorders.