The Deubiquitinating Enzyme Inhibitor PR-619 Enhances the Cytotoxicity of Cisplatin via the Suppression of Anti-Apoptotic Bcl-2 Protein: In Vitro and In Vivo Study
Kuan-Lin Kuo,
Shing-Hwa Liu,
Wei-Chou Lin,
Po-Ming Chow,
Yu-Wei Chang,
Shao-Ping Yang,
Chung-Sheng Shi,
Chen-Hsun Hsu,
Shih-Ming Liao,
Hong-Chiang Chang,
Kuo-How Huang
Affiliations
Kuan-Lin Kuo
Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei 100, Taiwan
Shing-Hwa Liu
Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei 100, Taiwan
Wei-Chou Lin
Department of Pathology, National Taiwan University Hospital, Taipei 100, Taiwan
Po-Ming Chow
Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei 100, Taiwan
Yu-Wei Chang
Department of Urology, College of Medicine, National Taiwan University, and National Taiwan University Hospital, Taipei 100, Taiwan
Shao-Ping Yang
Department of Urology, College of Medicine, National Taiwan University, and National Taiwan University Hospital, Taipei 100, Taiwan
Chung-Sheng Shi
Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
Chen-Hsun Hsu
Department of Urology, College of Medicine, National Taiwan University, and National Taiwan University Hospital, Taipei 100, Taiwan
Shih-Ming Liao
Department of Urology, College of Medicine, National Taiwan University, and National Taiwan University Hospital, Taipei 100, Taiwan
Hong-Chiang Chang
Department of Urology, College of Medicine, National Taiwan University, and National Taiwan University Hospital, Taipei 100, Taiwan
Kuo-How Huang
Department of Urology, College of Medicine, National Taiwan University, and National Taiwan University Hospital, Taipei 100, Taiwan
After chemotherapy for the treatment of metastatic bladder urothelial carcinoma (UC), most patients inevitably encounter drug resistance and resultant treatment failure. Deubiquitinating enzymes (DUBs) remove ubiquitin from target proteins and play a critical role in maintaining protein homeostasis. This study investigated the antitumor effect of PR-619, a DUBs inhibitor, in combination with cisplatin, for bladder UC treatment. Our results showed that PR-619 effectively induced dose- and time-dependent cytotoxicity, apoptosis, and ER-stress related apoptosis in human UC (T24 and BFTC-905) cells. Additionally, co-treatment of PR-619 with cisplatin potentiated cisplatin-induced cytotoxicity in UC cells and was accompanied by the concurrent suppression of Bcl-2. We also proved that Bcl-2 overexpression is related to the chemo-resistant status in patients with metastatic UC by immunohistochemistry (IHC) staining. In a xenograft mice model, we confirmed that PR-619 enhanced the antitumor effect of cisplatin on cisplatin-naïve and cisplatin-resistant UCs. Our results demonstrated that PR-619 effectively enhanced the cisplatin-induced antitumor effect via concurrent suppression of the Bcl-2 level. These findings provide promising insight for developing a therapeutic strategy for UC treatment.
