FOXM1 mediates ferroptosis and promotes cisplatin resistance in cervical cancer cells by up-regulating ELK1
Objective To investigate the effect and potential mechanism of FOXM1 on cisplatin(DDP)resistance in cervical cancer cells through ELK1.Methods The expressions of FOXM1 and ELK1 in cervical cancer tissues were analyzed by bioinformatics.The expressions of FOXM1 and ELK1 in cervical cancer cells were detected by qPCR.Double luciferase reporter gene experiment and ChIP experiment were performed to verify the combination of the two.ELK1 enrichment pathway was analyzed by GSEA.The correlation between ELK1 and the key genes of inhibiting ferroptosis was analyzed by Pearson correlation analysis.Cell viability was detected by CCK-8,and cell apoptosis was detected by PI staining and flow cytometry.The morphological changes of mitochondria were observed by transmission electron microscopy.Lipid Peroxidation(MDA)Assay kit was used to detect the MDA content.The expressions of GPX4,SLC7A11 and ACSL4 were detected by Werstern blot.Results ELK1 and FOXM1 were highly expressed in cervical cancer tissues and cells,and and there were binding sites for them.Compared with the oe-NC group,the cell survival rate and IC50 value of the oe-ELK1 group were significantly increased.Compared with the si-NC group,the cell survival rate and IC50 value of the si-ELK1 group were significantly decreased.Compared with the oe-NC+DMSO group,mitochondrial atrophy and mitochondrial ridge reduction were not observed in the oe-ELK1+DMSO group.Compared with the oe-ELK1+DMSO group,it showed obvious mitochondriaatrophy,mitochondrial ridge reduction or even disappearance in the oe-ELK1+erastin group.Compared with the oe-NC+DMSO group,intracellular MDA content was significantly decreased,the expressions of GPX4 and SLC7A11 proteins were increased,and the expression of ACSL4 protein was decreased in the oe-ELK1+DMSO group.And the use of erastin had reversed the above phenomenon.Compared with the oe-NC+DMSO group,the IC50 value of CaSki/DDP cells in the oe-ELK1+DMSO group was significantly increased,while the use of erastin had reduced the facilitation.In addition,compared with the si-NC+oe-NC group,the si-FOXM1+oe-NC group showed obvious mitochondriaatrophy,mitochondrial ridge reduction or even disappearance.Compared with the si-FOXM1+oe-NC group,the mitochondrial morphology was restored in the si-FOXM1+oe-ELK1 group.Compared with the si-NC+oe-NC group,the intracellular MDA content in the si-FOXM1+oe-NC group was significantly increased,the expressions of GPX4 and SLC7A11 protein were decreased,and the expression of ACSL4 protein was increased.Compared with the si-FOXM1+oe-NC group,the intracellular MDA contentin the si-FOXM1+oe-ELK1 group was significantly decreased,and the expressions of GPX4 and SLC7A11 protein were increased,while the expression of ACSL4 protein was decreased.Compared with the si-NC+oe-NC group,the IC50 value of CaSki/DDP cells in the si-FOXM1+oe-NC group was significantly decreased.Meanwhile,oe-ELK1 transfection has reversed the inhibition effect.Conclusion FOXM1 can mediate ferroptosis by up-regulating the expression of ELK1,thus promoting DDP resistance in cervical cancer cells.
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