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.
Highlights
Lung cancer is the most prevalent cancer and the leading cause of cancer-related death worldwide [1]
Three non–small cell lung carcinomas (NSCLCs) cell lines (A549, HCC827, NCI-H1299) were incubated with 0–10 μM WP1130 to determine the IC50 by Cell Counting Kit-8 (CCK-8) assay for 24 h, 48 h or 72 h (Supplementary Figure 1A–1B, Figure 1A)
Cell viability was significantly decreased in the co-treatment group, and the cisplatin IC50 in the A549 and HCC827 cells was 2.5 μM and 10 μM, respectively, higher than the IC50 of 1 μM and 5 μM in the A549 and HCC827 cells that had been treated with WP1130
Summary
Lung cancer is the most prevalent cancer and the leading cause of cancer-related death worldwide [1]. According to the National Central Cancer Registry of China, incidence and mortality attributable to lung cancer accounted for 73.33% of all new cancer cases and 61.02% of all cancer-related mortality, respectively [2]. Based on its histological characteristics, lung cancer is divided into small cell lung carcinomas (SCLCs) and non–small cell lung carcinomas (NSCLCs); the latter accounts for an estimated 85% of lung cancer cases [3] and commonly presents with progression. Molecular targeted therapies have demonstrated a positive effect in improving progression-free survival outcomes in patients with advanced NSCLC [4, 5], but the incidence of epidermal growth factor receptor (EGFR) mutation and the EML4-ALK fusion gene is approximately 10% and only 4%, respectively [6, 7]. Only a small proportion of patients with NSCLCs would benefit from molecular targeted therapies, and patients who do not present drug-targetable driver mutations mostly receive platinum-based chemotherapy
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