Ni Yinyun, Yang Ying, Zhang Li
Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610000, China.
Zhongguo Fei Ai Za Zhi. 2024 May 20;27(5):330-336. doi: 10.3779/j.issn.1009-3419.2024.101.12.
BACKGROUND: Targeted therapies are ineffective in lung squamous cancer (LUSC), and the low response rate of immunotherapy hampers its application in LUSC, so it is urgent to explore new strategies for LUSC treatment. Ferroptosis plays an important role in tumour suppression. The aim of this study was to investigate the role and mechanism of targeting 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) in regulating ferroptosis in LUSC cells, in order to provide a new research direction for LUSC therapy. METHODS: The expression of HMGCS1 in LUSC was analysed by The Cancer Genome Atlas (TCGA) and Clinical Proteomic Tumor Analysis Consortium (CPTAC) online databases; the relationship between HMGCS1 and survival time of lung cancer was analysed by the Kaplan-Meier Plotter online survival database; the expression level of HMGCS1 in LUSC tissues was verified by immunohistochemistry. After interfering with HMGCS1 expression by small interfering RNA (siRNA), cell activity and cell migration ability were detected by CCK8 and Transwell assay; apoptosis was detected by flow cytometry after interfering with HMGCS1 or after treatment with the HMGCS1 inhibitor of hymeglusin; Fe2+, reactive oxygen species (ROS) and lipid peroxidation levels were detected by flow cytometry and high-content confocal fluorescence imaging systems, respectively in SKMES cells after inhibition of HMGCS1; and Western blot was performed to detect the expression of ACSL4, GPX4 and SLC7A11, which are markers of the ferroptosis pathway after inhibition of HMGCS1. RESULTS: HMGCS1 mRNA and protein levels were significantly high in LUSC; siRNA interference with HMGCS1 expression inhibited the proliferative activity and migration ability of LUSC cells, but had no significant effect on apoptosis. Interference with HMGCS1 or treatment with the HMGCS1 inhibitor of hymeglusin significantly promoted intracellular Fe2+, ROS and lipid peroxidation levels in SKMES cells, and induced ferroptosis in LUSC cells; Western blot assay showed that inhibition of HMGCS1 significantly promoted the expression of ACSL4. CONCLUSIONS: Inhibition of HMGCS1, a target of LUSC, promotes ferroptosis in lung cancer cells and provides a research basis for screening new therapeutic targets for LUSC.
背景：靶向治疗在肺鳞状细胞癌（LUSC）中无效，免疫治疗的低反应率阻碍了其在LUSC中的应用，因此迫切需要探索LUSC治疗的新策略。铁死亡在肿瘤抑制中起重要作用。本研究旨在探讨靶向3-羟基-3-甲基戊二酰辅酶A合酶1（HMGCS1）在调节LUSC细胞铁死亡中的作用及机制，为LUSC治疗提供新的研究方向。 方法：通过癌症基因组图谱（TCGA）和临床蛋白质组肿瘤分析联盟（CPTAC）在线数据库分析HMGCS1在LUSC中的表达；通过Kaplan-Meier Plotter在线生存数据库分析HMGCS1与肺癌生存时间的关系；通过免疫组织化学验证LUSC组织中HMGCS1的表达水平。用小干扰RNA（siRNA）干扰HMGCS1表达后，采用CCK8和Transwell实验检测细胞活性和细胞迁移能力；干扰HMGCS1或用HMGCS1抑制剂海美格鲁辛处理后，通过流式细胞术检测细胞凋亡；在抑制HMGCS1后的SKMES细胞中，分别通过流式细胞术和高内涵共聚焦荧光成像系统检测Fe2+、活性氧（ROS）和脂质过氧化水平；进行蛋白质免疫印迹法检测抑制HMGCS1后铁死亡途径标志物ACSL4、GPX4和SLC7A11的表达。 结果：HMGCS1的mRNA和蛋白水平在LUSC中显著升高；siRNA干扰HMGCS1表达可抑制LUSC细胞的增殖活性和迁移能力，但对细胞凋亡无显著影响。干扰HMGCS1或用HMGCS1抑制剂海美格鲁辛处理可显著提高SKMES细胞内的Fe2+、ROS和脂质过氧化水平，并诱导LUSC细胞发生铁死亡；蛋白质免疫印迹法检测显示，抑制HMGCS1可显著促进ACSL4的表达。 结论：抑制LUSC的靶点HMGCS1可促进肺癌细胞铁死亡，为筛选LUSC新的治疗靶点提供了研究依据。
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