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WP1130 attenuates cisplatin resistance by decreasing P53 expression in non-small cell lung carcinomas.
- Source :
-
Oncotarget [Oncotarget] 2017 Jul 25; Vol. 8 (30), pp. 49033-49043. - Publication Year :
- 2017
-
Abstract
- 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.
- Subjects :
- Animals
Apoptosis drug effects
Carcinoma, Non-Small-Cell Lung metabolism
Cell Line, Tumor
Cell Proliferation drug effects
Cell Transformation, Neoplastic drug effects
Disease Models, Animal
Gene Expression Regulation, Neoplastic drug effects
Humans
Lung Neoplasms metabolism
Mice
Proteolysis
Tumor Suppressor Protein p53 metabolism
Ubiquitination
Xenograft Model Antitumor Assays
Carcinoma, Non-Small-Cell Lung genetics
Cisplatin pharmacology
Cyanoacrylates pharmacology
Drug Resistance, Neoplasm drug effects
Drug Resistance, Neoplasm genetics
Lung Neoplasms genetics
Pyridines pharmacology
Tumor Suppressor Protein p53 genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1949-2553
- Volume :
- 8
- Issue :
- 30
- Database :
- MEDLINE
- Journal :
- Oncotarget
- Publication Type :
- Academic Journal
- Accession number :
- 28446729
- Full Text :
- https://doi.org/10.18632/oncotarget.16931