Depletion of squalene epoxidase in synergy with glutathione peroxidase 4 inhibitor RSL3 overcomes oxidative stress resistance in lung squamous cell carcinoma

Abstract

Background: Lung squamous cell carcinoma (LUSC) lacks effective targeted therapies and has a poor prognosis. Disruption of squalene epoxidase (SQLE) has been implicated in metabolic disorders and cancer. However, the role of SQLE as a monooxygenase involved in oxidative stress remains unclear.

Methods: We analyzed the expression and prognosis of lung adenocarcinoma (LUAD) and LUSC samples from GEO and TCGA databases. The proliferative activity of the tumors after intervention of SQLE was verified by cell and animal experiments. JC-1 assay, flow cytometry, and Western blot were used to show changes in apoptosis after intervention of SQLE. Flow cytometry and fluorescence assay of ROS levels were used to indicate oxidative stress status.

Results: We investigated the unique role of SQLE expression in the diagnosis and prognosis prediction of LUSC. Knockdown of SQLE or treatment with the SQLE inhibitor terbinafine can suppress the proliferation of LUSC cells by inducing apoptosis and reactive oxygen species accumulation. However, depletion of SQLE also results in the impairment of lipid peroxidation and ferroptosis resistance such as upregulation of glutathione peroxidase 4. Therefore, prevention of SQLE in synergy with glutathione peroxidase 4 inhibitor RSL3 effectively mitigates the proliferation and growth of LUSC.

Conclusion: Our study indicates that the low expression of SQLE employs adaptive survival through regulating the balance of apoptosis and ferroptosis resistance. In future, the combinational therapy of targeting SQLE and ferroptosis could be a promising approach in treating LUSC.

Keywords

lung squamous cell carcinoma / squalene epoxidase / terbinafine / ROS / ferroptosis

Acknowledgements

We thank the Proteomics Platform of West China Hospital of Sichuan University for targeted metabolomics and the confocal microscope. This work was supported by the National Natural Science Foundation of China (Grant No. 92159302, W.L.); Science and Technology Project of Sichuan (Grant No. 2022ZDZX0018, W.L.); 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University (Grant No. ZYGD22009, W.L.). This work was also supported by National Key R&D program of China (Grant No. 2022YFC2505000), NSFC general program (Grant No. 82272796), NSFC special program (Grant No. 82241229), CAMS Innovation Fund for Medical Sciences (Grant No. CIFMS 2022-I2M-1-009), CAMS Key Laboratory of Translational Research on Lung Cancer (Grant No. 2018PT31035), and the Aiyou foundation (Grant No. KY201701).

Author contributions

Conceptualization: G.L., W.L. and J.W.; administrative support: J.W., W.L. and L.Z.; data analysis and curation: G.L. and L.C.; investigation and validation: L.Z. and H.B.; writing—original draft: G.L. and J.W.; funding acquisition: J.W. and W.L. All authors have read and agreed to the published version of the manuscript.

Supplementary data

Supplementary data are available at PCMEDI online.

Conflict of interest

None declared. As a co-Editor-in-Chief of Precision Clinical Medicine, the corresponding author W.L. was blinded from reviewing and making decision on this manuscript.

Ethics

This project was approved by the Ethics Committee of the Cancer Hospital of the Chinese Academy of Medical Sciences and West China Hospital of Sichuan University (Ethical code 20 221 230 001 and 2022/12/29 of approval). The animal experiment protocol was approved by the Animal Care and Use Committee of West China Hospital of Sichuan University and conform to the guidelines on the protection of animals used for scientific purposes.

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