https://scholars.lib.ntu.edu.tw/handle/123456789/590950
Title: | PR-619, a General Inhibitor of Deubiquitylating Enzymes, Diminishes Cisplatin Resistance in Urothelial Carcinoma Cells through the Suppression of c-Myc: An In Vitro and In Vivo Study | Authors: | Hsu, Fu-Shun WEI-CHOU LIN Kuo, Kuan-Lin Chiu, Yen-Ling Hsu, Chen-Hsun Liao, Shih-Ming Dong, Jun-Ren SHING-HWA LIU Chang, Shih-Chen Yang, Shao-Ping Chen, Yueh-Tang Chang, Ruei-Je KUO-HOW HUANG |
Keywords: | chemoresistance; deubiquitylating enzymes; urothelial carcinoma;Chemoresistance; Deubiquitylating enzymes; Urothelial carcinoma | Issue Date: | 28-Oct-2021 | Publisher: | MDPI | Journal Volume: | 22 | Journal Issue: | 21 | Source: | International Journal of Molecular Sciences | Abstract: | Cisplatin-based chemotherapy is the standard treatment for bladder urothelial carcinoma (UC). Most patients experience chemoresistance, the primary cause of treatment failure, which leads to disease relapse. The underlying mechanism of chemoresistance involves reduced apoptosis. In this study, we investigated the antitumor effect of the deubiquitylating enzyme inhibitor PR-619 in cisplatin-resistant bladder UC. Deubiquitinase (ubiquitin-specific protease 14 (USP14) and USP21) immunohistochemical staining demonstrated that deubiquitination is related to chemoresistance in patients with metastatic UC and may be a target for overcoming chemoresistance. Cytotoxicity and apoptosis were assessed using fluorescence-activated flow cytometry and a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium assay, and PR-619 was found to enhance the cytotoxic and apoptotic effects of cisplatin in cisplatin-resistant T24/R cells. Mitigated cisplatin chemoresistance was associated with the concurrent suppression of c-Myc expression in T24/R cells. Moreover, the expression of c-Myc was upregulated in human bladder UC specimens from patients with chemoresistance. Experiments in a xenograft nude mouse model confirmed that PR-619 enhanced the antitumor effects of cisplatin. These results are promising for the development of therapeutic strategies to prevent UC chemoresistance through the combined use of chemotherapeutic agents/deubiquitination inhibitors (PR-619) by targeting the c-Myc pathway. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/590950 | ISSN: | 16616596 | DOI: | 10.3390/ijms222111706 | SDG/Keyword: | 2,6-diaminopyridine-3,5-bis(thiocyanate); aminopyridine derivative; antineoplastic agent; cisplatin; deubiquitinase; thiocyanic acid derivative; ubiquitin thiolesterase; USP21 protein, human; animal; bladder tumor; carcinoma; drug effect; drug resistance; drug screening; human; metabolism; nude mouse; tumor cell line; Aminopyridines; Animals; Antineoplastic Agents; Carcinoma; Cell Line, Tumor; Cisplatin; Deubiquitinating Enzymes; Drug Resistance, Neoplasm; Humans; Mice, Nude; Thiocyanates; Ubiquitin Thiolesterase; Urinary Bladder Neoplasms; Xenograft Model Antitumor Assays |
Appears in Collections: | 醫學系 |
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