CISD1 knockdown enhances the sensitivity of non-small cell lung cancer cells to gefitinib by inducing ferroptosis
- VernacularTitle:CISD1敲低通过诱导铁死亡增强非小细胞肺癌对吉非替尼的敏感性
- Author:
Xiuyun LV
1
;
Hong SUO
1
;
Hui REN
1
Author Information
- Publication Type:Journal Article
- Keywords: lung cancer; drug resistance; gefitinib; CDGSH iron sulfur domain 1(CISD1); ferroptosis
- From: Journal of Xi'an Jiaotong University(Medical Sciences) 2025;46(3):426-434
- CountryChina
- Language:Chinese
- Abstract: Objective To investigate the role of CISD1 in gefitinib-resistant non-small cell lung cancer(NSCLC),so as to provide a potential therapeutic target for the treatment of gefitinib-resistant NSCLC.Methods Bioinformatics online platforms TIMER2.0 and HPA were used to analyze the expression level of CISD1 in lung cancer.TIMER2.0 and GEPIA2.0 were used to analyze the correlation between the expression levels of CISD1 and SLC7A11 in lung cancer.The correlation between CISD1 and overall survival rate of lung cancer patients was analyzed using KMPLOT.Human lung carcinoma cell line PC9 and gefitinib-resistant cell line PC9/GR were treated with gefitinib,and cell viability was detected using the CCK8 method.shCISD1 lentivirus infection was used to knockdown CISD1 in PC9/GR cells.Western blotting was employed to detect the protein expression levels of CISD1 and SLC7A11.PC9/GR cells were divided into shNC+DMSO group,shNC+gefitinib group,shCISD1 group,shCISD1+ferrostatin-1 group,and shCISD1+gefitinib group.Plate clone formation assay was used to detect cell proliferation capacity.FerroOrange fluorescent probe and C11-BODIPY fluorescent probe were used to detect intracellular free Fe2+content and intracellular lipid peroxide level,respectively.Results CISD1 was significantly overexpressed in lung carcinoma(P＜0.001).The expression level of CISD1 was negatively correlated with the overall survival rate of lung cancer patients and negatively correlated with the expression level of SLC7A11.Compared with the DMSO control group,gefitinib treatment significantly reduced clone formation and CISD1 protein expression levels in both PC9 and PC9/GR cells(P＜0.05),but the reduction was less pronounced in PC9/GR cells.shCISD1 infection significantly inhibited the protein expression levels of CISD1 and SLC7A11 in PC9/GR cells(P＜0.05)and enhanced the sensitivity of PC9/GR cells to gefitinib.Compared with the shNC+DMSO group,both the shNC+gefitinib group and the shCISD1 group showed significantly reduced clone formation ability(P＜0.05),but increased Fe2+and lipid peroxidation levels(P＜0.05).Compared with the shCISD1 group,the shCISD1+ferrostatin-1 group showed significantly increased clone formation ability(P＜0.05),but decreased Fe2+and lipid peroxidation levels(P＜0.05).Compared with the shNC+gefitinib group,the shCISD1+gefitinib group showed significantly reduced clone formation ability(P＜0.05),but increased Fe2+and lipid peroxidation levels(P＜0.05).Conclusion Knockdown of CISD1 promotes the sensitivity of NSCLC to gefitinib by inducing ferroptosis,which provides a new potential therapeutic target for the treatment of gefitinib-resistant NSCLC.
