Abstract
BACKGROUND/AIM: Upper tract urothelial carcinoma (UTUC) has a notably high incidence and aggressiveness in East Asian populations; however, its molecular mechanisms remain poorly defined. Our previous study identified 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase (ATIC), a bifunctional enzyme involved in de novo purine biosynthesis, as a tumor-promoting factor regulated by microRNA-145-5p in UTUC. Therefore, this study aimed to systematically investigate the functional interplay between ATIC and its downstream effectors in UTUC. MATERIALS AND METHODS: To elucidate ATIC-regulated signaling pathways, we performed tandem mass tag (TMT)-based quantitative proteomics in BFTC909 cells with ATIC knockdown, followed by functional, biochemical, and drug-sensitivity assays. RESULTS: Proteomic profiling identified B7-H3 (CD276), prion protein (PRNP), RAC2, and NT5E (CD73) as downstream molecules downregulated by ATIC silencing. Functional assays revealed that suppressing the expression of these proteins inhibited cell proliferation, migration, and invasion, and enhanced cisplatin sensitivity. RNA interference analysis indicated that B7-H3 may lie upstream of prion protein and RAC2. Mechanistically, the ATIC/B7-H3 axis were shown to modulate mTOR, AKT, ERK, and p38 phosphorylation, linking metabolic activity to oncogenic and chemoresistant signaling. CONCLUSION: These findings revealed an ATIC-associated metabolic-immunoregulatory network in UTUC, through which ATIC supports mTOR-related signaling and promotes tumor progression and cisplatin resistance. Targeting the ATIC-driven network may offer new therapeutic opportunities for UTUC management.