Mp65-17 Overcoming Cisplatin Resistance in Urothelial Carcinoma: The Role of Protein Deubiquitinase Inhibitors in Targeting Proliferating Cell Nuclear Antigen—a Combined in Vitro and in Vivo Approach

You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology III (MP65)1 May 2024MP65-17 OVERCOMING CISPLATIN RESISTANCE IN UROTHELIAL CARCINOMA: THE ROLE OF PROTEIN DEUBIQUITINASE INHIBITORS IN TARGETING PROLIFERATING CELL NUCLEAR ANTIGEN—A COMBINED IN VITRO AND IN VIVO APPROACH Tsae-Ni Lee, Jeff S. Chueh, Tsung-Yi Hsieh, Kuan Chong Ng, Ching-Ying Chang, and Shang-Jen Chang Tsae-Ni LeeTsae-Ni Lee , Jeff S. ChuehJeff S. Chueh , Tsung-Yi HsiehTsung-Yi Hsieh , Kuan Chong NgKuan Chong Ng , Ching-Ying ChangChing-Ying Chang , and Shang-Jen ChangShang-Jen Chang View All Author Informationhttps://doi.org/10.1097/01.JU.0001008756.24343.22.17AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Bladder urothelial carcinoma (UC) patients predominantly receive cisplatin-based chemotherapy as the frontline treatment, from muscle-invasive to locally advanced, unresectable, and metastatic stages. Yet, a considerable number of patients exhibit resistance, with diminished apoptosis being a primary contributor. Deubiquitinating enzymes play a key regulatory role in the apoptosis process. In addition, newly emerging evidence underscores the critical role of cancer stem cells (CSCs) in the initiation of cancer, its spread to other body parts, and its resistance to drugs. Targeting CSCs and deubiquitinases offers significant promise for advancing cancer therapy. In this study, we aim to investigate the potential mechanisms leading to chemoresistance in bladder UC cells and explore the possible benefits of VLX1570, an inhibitor of deubiquitinases UCHL5/USP14, which is currently in Phase I Clinical Trials. METHODS: We identified a subset of chemoresistant, cancer stem-like cells within UCs, known as T24/R cells. These cells were isolated through a drug-based selection process from the T24 cell line, which serves as a representative of bladder UCs. Immunohistochemical studies were conducted to assess the relationship between chemoresistance and deubiquitination activities. The impact of VLX1570 on these T24/R cells were accessed, and further mouse model experiments were performed for validation. RESULTS: Immunohistochemical studies pointed to a strong correlation between chemoresistance in metastatic UC patients and deubiquitination activities, particularly those of USP14 and UCHL5. In-depth assays revealed that VLX1570 enhances the cytotoxic and apoptosis-inducing effects of cisplatin in T24/R cells. Validation through mouse model experiments further emphasized the capability of VLX1570 to augment the antitumor action of cisplatin. CONCLUSIONS: Our study revealed that deubiquitination activities have a strong relationship with chemoresistance in metastatic UC, which highlights a promising strategy to tackle chemoresistance. Furthermore, VLX1570 enhances the cytotoxic and apoptosis-inducing effects of cisplatin, an effect that aligns with the downregulation of proliferating cell nuclear antigen (PCNA). Such insights set the stage for the development of innovative therapies that combine chemotherapy agents with VLX1570 to effectively address UC chemoresistance. Source of Funding: I have nothing to disclose © 2024 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 211Issue 5SMay 2024Page: e1083 Advertisement Copyright & Permissions© 2024 by American Urological Association Education and Research, Inc.Metrics Author Information Tsae-Ni Lee More articles by this author Jeff S. Chueh More articles by this author Tsung-Yi Hsieh More articles by this author Kuan Chong Ng More articles by this author Ching-Ying Chang More articles by this author Shang-Jen Chang More articles by this author Expand All Advertisement PDF downloadLoading ...