USP2 Reversed Cisplatin Resistance Through P53-mediated Ferroptosis in NSCLC

Overview

Journal BMC Med Genomics

Publisher Biomed Central

Specialty Genetics

Date 2025 Feb 26

PMID 40011884

Authors

Yanmei Gong

Ruichao Li

Rui Zhang

Li Jia

Affiliations

Soon will be listed here.

Abstract

Background: It has demonstrated the indispensable role of ferroptosis in conferring cisplatin resistance in non-small cell lung cancer (NSCLC), as well as the involvement of ubiquitin-specific protease (USP) in regulating ferroptosis. This paper aspired to the mechanism of USP2 and ferroptosis on NSCLC cisplatin resistance.

Methods: Ubiquitin-specific protease mRNA expression, was detected through RT-qPCR. In vitro functional assays assessed the effects of USP2 overexpression on DDP resistance, cell proliferation capability, and ferroptosis markers in A549/DDP and H1299/DDP cells. Ubiquitination assays evaluated the ubiquitination levels of p53 following USP2 overexpression. Co-immunoprecipitation (Co-IP) assays confirmed the binding relationship between USP2 and p53. In vivo experiments in mice explored the specific role of the USP2-p53 axis in a xenograft tumor model.

Results: USP2 expression was suppressed in cisplatin-resistant NSCLC cells. USP2 overexpression inhibited cell viability in cisplatin-resistant cells. Among the ferroptosis markers, the results showed that USP2 overexpression promoted LDH release, Fe level, MDA and Lipid ROS, while inhibited GPX4 activity and GSH levels. The WB results revealed that USP2 overexpression inhibited GPX4, SLC7A11 and cytoplasm p53 protein expression, while promoted the nucleus p53 protein expression. Moreover, USP2 directly bound to p53 and USP2 overexpression stabilized p53 protein by suppressing its ubiquitination. In vivo experiments further suggest that the USP2-p53 pathway plays a crucial role in regulating cisplatin sensitivity in A549/DDP cells.

Conclusion: USP2 acted on the K305R site of p53, which resulted in its deubiquitination. This cellular process could modulate cisplatin resistance through ferroptosis in NSCLC. This study could provide a potential therapeutic target to NSCLC.

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