Microsomal glutathione transferase ۱ confers cisplatin resistance of non-small cell lung cancer via interaction with arachidonate lipoxygenase ۵ to repress ferroptosis

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 ۱ (MGST۱) expression has been found in DDP-resistant NSCLC cells. This study aimed to explore the function and mechanism of MGST۱ 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-۸ (CCK-۸) and colony formation assays. Ferroptosis was determined by malondialdehyde (MDA), glutathione (GSH), Fe۲+, and reactive oxygen species (ROS) levels. The interaction between proteins was confirmed by Co-immunoprecipitation (Co-IP). The effect of MGST۱ on DDP resistance was evaluated using the tumor xenograft assay in vivo. Immunohistochemical staining was performed to measure Ki-۶۷ and p-H۲A.X expression in tumor tissues.Results: MGST۱ expression was higher, while arachidonate lipoxygenase ۵ (ALOX۵) expression was lower in DDP-resistant NSCLC patients and cells. MGST۱ ablation sensitized NSCLC cells to DDP therapy through inducing ferroptosis. MGST۱ protein directly interacted with ALOX۵ protein to restrain ALOX۵-triggered ferroptosis. Ferroptosis inhibitor or sh-ALOX۵ reversed the promotive effect of MGST۱ silencing on the DDP sensitivity of NSCLC cells. Finally, MGST۱ depletion sensitized NSCLC cells to DDP therapy in nude mice in vivo.Conclusion: MGST۱ high expression contributed to DDP resistance of NSCLC cells by inhibiting ALOX۵-induced ferroptosis. Our results provide a potential therapeutic target for overcoming DDP resistance in NSCLC patients.

کلیدواژه ها:

Acetylsalicylic acid ، Antioxidants ، Epididymis ، Melatonin ، Sperm ، Testosterone