Department of Thoracic Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China.
Environ Toxicol. 2024 Jul;39(7):4035-4046. doi: 10.1002/tox.24272. Epub 2024 Apr 20.
Non-small cell lung cancer (NSCLC) is a prevailing LC characterized by poor outcomes. AlkB homolog 5 (ALKBH5) functions as a tumor suppressor in several cancers. This study delved into the role of ALKBH5 in NSCLC development.
TCGA database predicted ALKBH5 expression in NSCLC patients. ALKBH5 levels in NSCLC and human bronchial epithelial cells were determined. pcDNA3.1-ALKBH5/NC, pcDNA3.1-SLC7A11/NC, and ferrostatin-1 were used to explore the interactions among ALKBH5, SLC7A11, and ferroptosis. SLC7A11 mRNA and its protein levels were measured by RT-qPCR and Western blot. Cell viability, apoptosis, migration, and invasion were assessed by CCK-8, flow cytometry, and Transwell. Total N6-methyladenosine (m6A) quantification and its enrichment on SLC7A11 mRNA were determined, followed by the observation of Ki67, ALKBH5 and SLC7A11-positive cell numbers. Glutathione (GSH), lipid reactive oxygen species (lipid-ROS), malondialdehyde (MDA), and iron ion contents were determined. Animal experiments further analyzed the role of ALKBH5 in tumor development and glutathione peroxidase 4 (GPX4) expression.
Bioinformatics analysis revealed the lowly-expressed ALKBH5 in LC patients. ALKBH5 was downregulated in NSCLC cells and its upregulation repressed proliferation activity, invasion, and migration, and facilitated apoptosis. ALKBH5 upregulation decreased GSH, increased lipid-ROS, MDA, and iron ion contents, and downregulated SLC7A11 by reducing m6A modification. SLC7A11 upregulation partly annulled the effect of ALKBH5 overexpression on cell ferroptosis and malignant behaviors. In vivo assays elucidated the suppression of ALKBH5 upregulation on tumor development and GPX4 levels.
ALKBH5 upregulation downregulates SLC7A11 transcription by decreasing m6A modification, thus promoting NSCLC cell ferroptosis and ultimately repressing NSCLC progression.
非小细胞肺癌（NSCLC）是一种预后较差的肺癌，ALKBH5 作为一种肿瘤抑制因子在多种癌症中发挥作用。本研究探讨了 ALKBH5 在 NSCLC 发展中的作用。
TCGA 数据库预测 NSCLC 患者中 ALKBH5 的表达。检测 NSCLC 和人支气管上皮细胞中 ALKBH5 的水平。使用 pcDNA3.1-ALKBH5/NC、pcDNA3.1-SLC7A11/NC 和 ferrostatin-1 来探讨 ALKBH5、SLC7A11 和铁死亡之间的相互作用。通过 RT-qPCR 和 Western blot 测量 SLC7A11 mRNA 及其蛋白水平。通过 CCK-8、流式细胞术和 Transwell 评估细胞活力、凋亡、迁移和侵袭。测定总 N6-甲基腺苷（m6A）的定量及其在 SLC7A11 mRNA 上的富集，然后观察 Ki67、ALKBH5 和 SLC7A11 阳性细胞的数量。测定谷胱甘肽（GSH）、脂质活性氧（lipid-ROS）、丙二醛（MDA）和铁离子含量。动物实验进一步分析了 ALKBH5 在肿瘤发展和谷胱甘肽过氧化物酶 4（GPX4）表达中的作用。
生物信息学分析显示 LC 患者中 ALKBH5 表达水平较低。ALKBH5 在 NSCLC 细胞中下调，其上调抑制增殖活性、侵袭和迁移，并促进凋亡。ALKBH5 上调降低了 GSH，增加了脂质-ROS、MDA 和铁离子含量，并通过降低 m6A 修饰下调了 SLC7A11。SLC7A11 的上调部分抵消了 ALKBH5 过表达对细胞铁死亡和恶性行为的影响。体内实验阐明了 ALKBH5 上调抑制肿瘤发展和 GPX4 水平的作用。
ALKBH5 上调通过降低 m6A 修饰下调 SLC7A11 转录，从而促进 NSCLC 细胞铁死亡，最终抑制 NSCLC 进展。
