肺癌上皮间质转化对铁死亡药物的敏感性研究

The effect of epithelial-mesenchymal transition on the sensitivity of ferroptosis inducers in lung cancer

目的研究肺癌上皮间质转化(EMT)对铁死亡药物敏感性的影响。方法利用生物信息学分析EMT相关基因与多种药物治疗敏感性的相关性;利用流式细胞分选出E-钙黏蛋白低表达且N-钙黏蛋白高表达、E-钙黏蛋白高表达且N-钙黏蛋白低表达的细胞,进而模拟肺癌间质细胞和上皮细胞;通过铁死亡诱导剂(谷胱甘肽过氧化物酶4抑制剂)和内源性铁死亡诱导剂(干扰素γ联合花生四烯酸)处理肺癌细胞,检测比较不同类型肺癌细胞对铁死亡的敏感性。结果细胞对铁死亡的耐受程度与E-钙黏蛋白的表达呈正相关,与波形蛋白、锌指结构E-box-结合同源框1、锌指结构E-box-结合同源框2的表达呈负相关。铁死亡药物处理结果显示E-钙黏蛋白低表达且N-钙黏蛋白高表达的细胞对铁死亡药物具有更高的敏感性,并且可以通过铁死亡抑制剂铁抑素-1挽救干扰素γ联合花生四烯酸对细胞铁死亡的诱导作用。结论发生EMT的肺癌细胞对铁死亡更加敏感,铁死亡有望成为应对转移和治疗抵抗性肺癌的新策略。

Objective To investigate the effect of epithelial-mesenchymal transition(EMT)on the sensitivity to ferroptosis inducers in lung cancer.Methods Bioinformatics analysis was utilized to assess the relationship between EMT-related genes and the sensitivity of multiple drugs.Cells with low expression of E-cadherin and high expression of N-cadherin or high expression of E-cadherin and low expression of N-cadherin were sorted by flow cytometry to simulate lung cancer epithelial and mesenchymal cells.The sensitivity of different types of lung cancer cells to ferroptosis was compared by treatment with the ferroptosis inducer(GPX4)and endogenous ferroptosis inducers(IFN-γcombined with arachidonic acid).Results The resistance to ferroptosis inducers was positively correlated with the expression of E-cadherin and negatively correlated with the expression of vimentin,zinc finger E-box-binding homeobox 1 and zinc finger E-box-binding homeobox 2.Treatment with ferroptosis-inducers revealed that lung cancer cells with low expression of E-cadherin and high expression of N-cadherin were more sensitive to ferroptosis.The ferroptosis inhibitor ferrostatin-1 could reverse the induction of ferroptosis by IFN-γcombined with arachidonic acid.Conclusion Lung cancer cells undergoing EMT are more sensitive to ferroptosis,which could potentially serve as a novel therapeutic strategy for the treatment of metastatic and treatment-resistant lung cancer.