WP1130 attenuates cisplatin resistance by decreasing P53 expression in non-small cell lung carcinomas

Abstract

Cisplatin-based combination chemotherapy markedly enhances survival rates in non-small cell lung carcinomas (NSCLCs), but drug resistance often leads to disease progression and relapse. Recent research has highlighted the role of deubiquitinases (DUBs) in regulating tumor cell growth, apoptosis, and chemoresistance. This study aimed to explore how WP1130, a DUB inhibitor, influences cisplatin sensitivity in NSCLCs. When WP1130 was combined with cisplatin, sensitivity to the drug increased significantly in A549 and HCC827 cells with reduced p53 expression, thereby inhibiting their proliferation. However, this effect was not observed in p53-deficient NCI-H1299 cells. The enhanced cytotoxicity of the cisplatin-WP1130 combination was lost in cells with p53 knockdown. Western blot analysis confirmed the reduction in p53 expression in A549 and HCC827 cells treated with cisplatin and WP1130. The effects of WP1130 on decreasing p53 expression were reversed by either administering MG132, a proteasome inhibitor, or knocking down ubiquitin-specific peptidase 9, X-linked (USP9X). These results suggest that WP1130 may improve the efficacy of cisplatin-based chemotherapy in NSCLCs through a mechanism involving USP9X-mediated p53 ubiquitination and Degrasyn degradation.