WP1130 attenuates cisplatin resistance by decreasing P53 expression in non–small cell lung carcinomas
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Xiang Wang1,2,3,#, Ying Bao2,#, Zhaohui Dong2, Qiuqiang Chen2, Huihui Guo2, Charlie Ziang3,* and Jianzhong Shao1,*
1College of Life Sciences, Zhejiang University, Hangzhou 310058, People’s Republic of China
2Key Laboratory for Translational Medicine, First Affiliated Hospital, Huzhou University, Huzhou 313000, People’s Republic of China
3State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310058, People’s Republic of China
*These authors contributed equally to this work
#These authors share first authorship
Jianzhong Shao, email: email@example.com
Charlie Ziang, email: firstname.lastname@example.org
Keywords: non-small cell lung carcinomas, WP1130, cisplatin, p53, USP9X
Received: November 10, 2016 Accepted: March 24, 2017 Published: April 07, 2017
Cisplatin-based combination chemotherapy significantly improves the survival outcomes in non–small cell lung carcinomas (NSCLCs), but drug resistance commonly contributes to disease progression and relapse. Recently, accumulating evidence has indicated that deubiquitinases (DUBs) are involved in regulating tumor cell proliferation, apoptosis, and chemoresistance. We designed this study to investigate the role of WP1130, a DUB inhibitor, in regulating cisplatin cytotoxicity in NSCLCs. After being combined with WP1130, cisplatin sensitivity was significantly increased in A549 and HCC827 cells with decreased p53 expression, inhibiting their proliferation, but not in p53-deficient NCI-H1299 cells. The synergistic cytotoxicity of the cisplatin and WP1130 co-treatment was abolished in p53-knockdown cells. Western blotting verified the decreased p53 expression in A549 and HCC827 cells treated with cisplatin and WP1130. The administration of MG132, a proteasome inhibitor, or knockdown of ubiquitin-specific peptidase 9, X-linked (USP9X) both eliminated the effect of WP1130 in decreasing p53 expression. Taken together, our findings confirm that the inclusion of WP1130 is potentially contributes to better therapeutic effects of cisplatin-based chemotherapy of NSCLCs in a manner dependent on the USP9X–p53 ubiquitination–mediated degradation pathway.
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