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
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
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DOI：
10.3390/cells8101268
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发表时间：
2019-10-01
期刊：
影响因子：
6
通讯作者：
Huang, Kuo-How
中科院分区：
文献类型：
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作者：
Kuo, Kuan-Lin;Liu, Shing-Hwa;Huang, Kuo-How
转移性膀胱尿路上皮癌（UC）化疗后，大多数患者不可避免地遇到耐药性，从而导致治疗失败。去泛素化酶（DUBs）是将泛素从靶蛋白上去除的酶，在维持蛋白质稳态中起着关键作用。本研究探讨了DUBs抑制剂PR-619与顺铂联合治疗膀胱UC的抗肿瘤作用。我们的研究结果表明，PR-619有效地诱导剂量和时间依赖性的细胞毒性，细胞凋亡，ER应激相关的细胞凋亡在人类UC（T24和BFTC-905）细胞。此外，PR-619与顺铂联合处理可增强顺铂诱导的UC细胞毒性，并同时抑制Bcl-2。我们还通过免疫组化（IHC）染色证实了Bcl-2过表达与转移性UC患者的化疗耐药状态有关。在异种移植小鼠模型中，我们证实PR-619增强了顺铂对顺铂初始和顺铂耐药UC的抗肿瘤作用。我们的结果表明，PR-619有效地增强顺铂诱导的抗肿瘤作用，通过同时抑制Bcl-2水平。这些发现为开发UC治疗的治疗策略提供了有希望的见解。
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-naive 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.