Microsomal glutathione transferase 1 confers cisplatin resistance of non-small cell lung cancer via interaction with arachidonate lipoxygenase 5 to repress ferroptosis

Document Type : Original Article

Authors

1 Department of Thoracic Surgery, Cangzhou Central Hospital, Cangzhou061000, Hebei Province, P.R. China

2 Department of Oncology, North China Petroleum General Hospital, Cangzhou062550, Hebei Province, P.R. China

3 Department of Thoracic Surgery, Cangzhou People’s Hospital, Cangzhou061000, Hebei Province, P.R. China

4 Department of Thoracic Surgery, Huanghua People’s Hospital, Cangzhou061100, Hebei Province, P.R. China

5 Department of Oncology, Cangzhou Central Hospital, Cangzhou061000, Hebei Province, P.R. China

10.22038/ijbms.2024.79203.17160

Abstract

Objective(s): Cisplatin (DDP) resistance remains a primary cause of chemotherapy failure and recurrence of non-small cell lung cancer (NSCLC). Abnormal high microsomal glutathione transferase 1 (MGST1) expression has been found in DDP-resistant NSCLC cells. This study aimed to explore the function and mechanism of MGST1 in DDP resistance of NSCLC cells.
Materials and Methods: The expression levels of target molecules were assessed by quantitative real-time polymerase chain reaction (RT-qPCR) and western blotting. Cell proliferation was evaluated by cell counting kit-8 (CCK-8) and colony formation assays. Ferroptosis was determined by malondialdehyde (MDA), glutathione (GSH), Fe2+, and reactive oxygen species (ROS) levels. The interaction between proteins was confirmed by Co-immunoprecipitation (Co-IP). The effect of MGST1 on DDP resistance was evaluated using the tumor xenograft assay in vivo. Immunohistochemical staining was performed to measure Ki-67 and p-H2A.X expression in tumor tissues.
Results: MGST1 expression was higher, while arachidonate lipoxygenase 5 (ALOX5) expression was lower in DDP-resistant NSCLC patients and cells. MGST1 ablation sensitized NSCLC cells to DDP therapy through inducing ferroptosis. MGST1 protein directly interacted with ALOX5 protein to restrain ALOX5-triggered ferroptosis. Ferroptosis inhibitor or sh-ALOX5 reversed the promotive effect of MGST1 silencing on the DDP sensitivity of NSCLC cells. Finally, MGST1 depletion sensitized NSCLC cells to DDP therapy in nude mice in vivo.
Conclusion: MGST1 high expression contributed to DDP resistance of NSCLC cells by inhibiting ALOX5-induced ferroptosis. Our results provide a potential therapeutic target for overcoming DDP resistance in NSCLC patients.

Keywords

Main Subjects

References

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Iranian Journal of Basic Medical Sciences
Volume 28, Issue 2
February 2025
Pages 209-216

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