UPP1 enhances bladder cancer progression and gemcitabine resistance through AKT

作者：Wenzhi Du, Sheng Tu, Wenxiu Zhang, Yi Zhang, Wei Liu, Kangping Xiong, Fenfang Zhou, Na Li, Renjie Zhang, Jingtian Yu, Mingxing Li, Wan Xiang, Kaiyu Qian, Gang Wang, Yu Xiao, Xinghuan Wang, Lingao Ju · 发表于：International Journal of Biological Sciences · 年份：2024 · DOI：10.7150/ijbs.83774 · 被引用次数：51 · 研究领域：Cancer, Hypoxia, and Metabolism、Biochemical and Molecular Research、RNA modifications and cancer

UPP1, a crucial pyrimidine metabolism-related enzyme, catalyzes the reversible phosphorylation of uridine to uracil and ribose-1-phosphate. However, the effects of UPP1 in bladder cancer (BLCA) have not been elucidated. AKT, which is activated mainly through dual phosphorylation (Thr308 and Ser473), promotes tumorigenesis by phosphorylating downstream substrates. This study demonstrated that UPP1 promotes BLCA cell proliferation, migration, invasion, and gemcitabine resistance by activating the AKT signaling pathway in vitro and in vivo. Additionally, UPP1 promoted AKT activation by facilitating the binding of AKT to PDK1 and PDK2 and the recruitment of phosphatidylinositol 3,4,5-triphosphate to AKT. Moreover, the beneficial effects of UPP1 on BLCA tumorigenesis were mitigated upon UPP1 mutation with Arg94 or MK2206 treatment (AKT-specific inhibitor). AKT overexpression or SC79 (AKT-specific activator) treatment restored tumor malignancy and drug resistance. Thus, this study revealed that UPP1 is a crucial oncogene and a potential therapeutic target for BLCA and that UPP1 activates the AKT signaling pathway and enhances tumorigenesis and drug resistance to gemcitabine.