PAICS as a potential target for cancer therapy linking purine biosynthesis to cancer progression

Tumor cells are required to undergo metabolic reprogramming for rapid development and progression, and one of the metabolic characteristics of cancer cells is the excessive synthesis and utilization of nucleotides. Abnormally increased nucleotides and their metabolites not only directly accelerate tumor cell progression but also indirectly act on stromal cells in the tumor microenvironment (TME) via a paracrine manner to regulate tumor progression. Purine nucleotides are mainly produced via de novo nucleotide synthesis in tumor cells; therefore, intervening in their synthesis has emerged as a promising strategy in anti-tumor therapy. De novo purine synthesis is a 10-step reaction catalyzed by six enzymes to synthesize inosine 5-monophosphate (IMP) and subsequently synthesize AMP and GMP. Phosphoribosylaminoimidazole carboxylase/phosphori-bosylaminoimidazole succinocarboxamide synthetase (PAICS) is a bifunctional enzyme that catalyzes de novo purine synthesis. Aberrantly elevated PAICS expression in various tumors is associated with poor prognosis. Evidence suggests that PAICS and its catalytic product, N-succinylcarboxamide-5-aminoimidazole ribonucleotide (SAICAR), could inhibit tumor cell apoptosis and promote the growth, epithelial-mesenchymal transition (EMT), invasion, and metastasis by regulating signaling pathways such as pyruvate kinase M2 (PKM2), extracellular signal-related kinases 1 and 2 (ERK1/2), focal adhesion kinase (FAK) and so on. This review summarizes the structure, biological functions and the molecular mechanisms of PAICS in cancer development and discusses its potential to be a target for tumor therapy.