2. Academic Validation
  3. UPP1 enhances bladder cancer progression and gemcitabine resistance through AKT

UPP1 enhances bladder cancer progression and gemcitabine resistance through AKT

  • Int J Biol Sci. 2024 Jan 27;20(4):1389-1409. doi: 10.7150/ijbs.83774.
Wenzhi Du 1 2,  Sheng Tu 1 3,  Wenxiu Zhang 4,  Yi Zhang 5 6,  Wei Liu 7,  Kangping Xiong 1 3,  Fenfang Zhou 8,  Na Li 9,  Renjie Zhang 1 3,  Jingtian Yu 1 3,  Mingxing Li 3,  Wan Xiang 10,  Kaiyu Qian 1 10,  Gang Wang 3 10,  Yu Xiao 3 10,  Xinghuan Wang 3 11,  Lingao Ju 1 10
Affiliations

Affiliations

  • 1 Hubei Key Laboratory of Urological Diseases, Laboratory of Precision Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China.
  • 2 Department of Urology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Medicine and Health Key Laboratory of Organ Transplantation and Nephrosis, Shandong Institute of Nephrology, Jinan, Shandong, China.
  • 3 Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China.
  • 4 Department of Pediatrics, Maternal and Child Health Care Hospital of Shandong Province, Jinan, China.
  • 5 Euler Technology, ZGC Life Sciences Park, Beijing, China.
  • 6 Center for Quantitative Biology, School of Life Sciences, Peking University, Beijing, China.
  • 7 Department of Urology, Aerospace Center Hospital, Peking University Aerospace School of Clinical Medicine, Beijing, China.
  • 8 Department of Radiology, Zhongnan Hospital of Wuhan University, Wuhan, China.
  • 9 State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, SunYat-sen University, Guangzhou, China.
  • 10 Department of Biological Repositories, Human Genetic Resources Preservation Center of Hubei Province, Zhongnan Hospital of Wuhan University, Wuhan, China.
  • 11 Medical Research Institute, Frontier Science Center of Immunology and Metabolism, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, China.
PMID: 38385072 DOI: 10.7150/ijbs.83774
Abstract

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.

Keywords

AKT; UPP1; bladder cancer.; gemcitabine; metastasis.

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