Luo_2025_Anticancer.Res_45_1001

BACKGROUND/AIM: Dipeptidyl peptidase-4 (DPP4) inhibitors like sitagliptin are recognized for their therapeutic role in diabetes. Elevated levels of DPP4 are strongly linked to the clinical aggressiveness of upper tract urothelial carcinoma (UTUC). However, sitagliptin's impact on UTUC is poorly understood and requires further research. PATIENTS AND METHODS: This research utilized real-time PCR and immunohistochemistry to measure DPP4 mRNA and protein expression in UTUC. Sitagliptin's effects on cell proliferation and apoptosis were assessed using the alamarBlue assay and annexin V staining in UTUC cell lines. Migration ability was evaluated through wound-healing and transwell migration assays. The combined effect of sitagliptin and cisplatin on UTUC cell viability was also examined using both UTUC cell lines and patient-derived organoids. RESULTS: Elevated DPP4 expression correlates with advanced tumor stages and reduced cancer-specific survival in UTUC. Sitagliptin treatment significantly reduced cell proliferation and enhanced apoptosis. Moreover, sitagliptin inhibited UTUC cell migration. Western blot results showed that sitagliptin treatment led to increased levels of apoptotic markers and reduced phosphorylation of AKT. It also influenced the phenotypical markers associated with epithelial-mesenchymal transition. Adding sitagliptin to cisplatin therapy did not show diminished antitumor efficacy compared with the effects of cisplatin alone. CONCLUSION: Sitagliptin inhibits the proliferation and migration of UTUC cells, promotes apoptosis, and influences the phenotypical transition from mesenchymal to epithelial states, likely via modulation of the AKT pathway. Sitagliptin may not cause chemotherapy resistance when combined with cisplatin treatment. These findings highlight its potential as an adjuvant therapy in UTUC.