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

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 in...

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Autores principales:	Fu-Shun Hsu, Wei-Chou Lin, Kuan-Lin Kuo, Yen-Ling Chiu, Chen-Hsun Hsu, Shih-Ming Liao, Jun-Ren Dong, Shing-Hwa Liu, Shih-Chen Chang, Shao-Ping Yang, Yueh-Tang Chen, Ruei-Je Chang, Kuo-How Huang
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	deubiquitylating enzymes urothelial carcinoma chemoresistance Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/d9994980aac0429085cecb8fda0d6e8e
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spelling	oai:doaj.org-article:d9994980aac0429085cecb8fda0d6e8e2021-11-11T17:09:57ZPR-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 Study10.3390/ijms2221117061422-00671661-6596https://doaj.org/article/d9994980aac0429085cecb8fda0d6e8e2021-10-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/11706https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Cisplatin-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.Fu-Shun HsuWei-Chou LinKuan-Lin KuoYen-Ling ChiuChen-Hsun HsuShih-Ming LiaoJun-Ren DongShing-Hwa LiuShih-Chen ChangShao-Ping YangYueh-Tang ChenRuei-Je ChangKuo-How HuangMDPI AGarticledeubiquitylating enzymesurothelial carcinomachemoresistanceBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 11706, p 11706 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	deubiquitylating enzymes urothelial carcinoma chemoresistance Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	deubiquitylating enzymes urothelial carcinoma chemoresistance Biology (General) QH301-705.5 Chemistry QD1-999 Fu-Shun Hsu Wei-Chou Lin Kuan-Lin Kuo Yen-Ling Chiu Chen-Hsun Hsu Shih-Ming Liao Jun-Ren Dong Shing-Hwa Liu Shih-Chen Chang Shao-Ping Yang Yueh-Tang Chen Ruei-Je Chang Kuo-How Huang 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
description	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.
format	article
author	Fu-Shun Hsu Wei-Chou Lin Kuan-Lin Kuo Yen-Ling Chiu Chen-Hsun Hsu Shih-Ming Liao Jun-Ren Dong Shing-Hwa Liu Shih-Chen Chang Shao-Ping Yang Yueh-Tang Chen Ruei-Je Chang Kuo-How Huang
author_facet	Fu-Shun Hsu Wei-Chou Lin Kuan-Lin Kuo Yen-Ling Chiu Chen-Hsun Hsu Shih-Ming Liao Jun-Ren Dong Shing-Hwa Liu Shih-Chen Chang Shao-Ping Yang Yueh-Tang Chen Ruei-Je Chang Kuo-How Huang
author_sort	Fu-Shun Hsu
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
title_short	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
title_full	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
title_fullStr	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
title_full_unstemmed	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
title_sort	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
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/d9994980aac0429085cecb8fda0d6e8e
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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

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