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miR-324-3p reverses cisplatin resistance by inducing GPX4-mediated ferroptosis in lung adenocarcinoma cell line A549

2021; Elsevier BV; Volume: 549; Linguagem: Inglês

10.1016/j.bbrc.2021.02.077

1090-2104

Shihua Deng, Dongming Wu, Li Li, Teng Liu, Ting Zhang, Jing Li, Ye Yu, Miao He, Yangyang Zhao, Rong Han, Ying Xu,

MicroRNA in disease regulation

MicroRNAs act as crucial regulators of a diverse range of biological processes, including chemoresistance. Our study aimed to investigate the effect of miR-324-3p on lung adenocarcinoma cell line A549 resistant to cis-diamminedichloroplatinum II (DDP, aka cisplatin). The miR-324-3p expression levels in cisplatin-sensitive A549(A549) and cisplatin-resistant A549 (A549/DDP) cells were determined by qRT-PCR assay. Cell proliferation was determined with the commercial kit CCK-8 and colony formation assay, whereas cell death was analyzed using flow cytometry. The target gene of miR-324-3p was identified and validated with the luciferase reporter and western blot assays. The role of miR-324-3p in modulating cisplatin resistance was evaluated in vitro. The expression of miR-324-3p was found to be significantly downregulated in the A549/DDP cells. Conversely, miR-324-3p overexpression reversed cisplatin resistance in the cells. With regard to the possible mechanism underlying this phenomenon, we identified the glutathione peroxidase 4 (GPX4) gene as the direct target of miR-324-3p, where overexpression of the gene reversed the miR-324-3p effect of sensitizing the A549/DDP cells to cisplatin. Furthermore, the GPX4 inhibitor RSL3 could mimic the effect of miR-324-3p upregulation in increasing the sensitivity of the cisplatin-resistant cells to the drug. Significantly, miR-324-3p enhanced cisplatin-induced ferroptosis in the A549/DDP cells. Our findings revealed the role of the miR-324-3p–GPX4 signaling axis in A549/DDP cells and how the targeting of this axis could be a potential strategy for reversing cisplatin resistance in human non small cell lung cancer (NSCLC).