Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Diseases, Tianjin Key Laboratory of Cerebral Blood Flow Reconstruction and Head and Neck Tumour New Technology Translation, Tianjin Neurosurgical Institute, Tianjin Huanhu Hospital, Tianjin 300350, China.
Clinical College of Neurology, Neurosurgery and Neurorehabilitation, Tianjin Medical University, Tianjin 300070, China.
Carcinogenesis. 2024 Jul 8;45(7):487-499. doi: 10.1093/carcin/bgae016.
Ferroptosis is a new form of regulated cell death caused by the iron-dependent peroxidation of phospholipids and is related to cell metabolism, redox homeostasis and various signalling pathways related to cancer. The long non-coding RNA (lncRNA) KB-1460A1.5 acts as a tumour suppressor gene to regulate tumour growth in gliomas, but its molecular network regulatory mechanism is still unclear. In this study, we found that KB-1460A1.5 can induce ferroptosis in glioma and enhance sensitivity to RSL3, a ferroptosis inducer. Tandem mass tag proteomics and nontargeted metabolomics suggest that KB-1460A1.5 affects polyunsaturated fatty acid metabolic processes. Gas chromatography-mass spectrometry-based medium- and long-chain fatty acid-targeted metabolomics confirmed that upregulation of KB-1460A1.5 decreased the levels of monounsaturated fatty acids, oleic acid (OA) and palmitoleic acid (PO) in glioma cells. The addition of OA and PO restored KB-1460A1.5-induced cellular ferroptosis. Molecularly, KB-1460A1.5 inhibited the mammalian target of rapamycin signalling pathway to suppress the expression of downstream sterol regulatory element-binding protein 1 (SREBP-1), thereby attenuating the stearoyl-CoA desaturase-1 (SCD1)-mediated desaturation of polyunsaturated fatty acids. Finally, an animal model of subcutaneous glioma confirmed that KB-1460A1.5 could inhibit tumour progression, SREBP-1/SCD1 expression and ferroptosis. In conclusion, increasing the expression level of KB-1460A1.5 in glioma can promote the induction of oxidative stress and ferroptosis in cancer cells through SREBP-1/SCD1-mediated adipogenesis, demonstrating therapeutic potential in preclinical models.
铁死亡是一种新的受铁依赖性磷脂过氧化调控的细胞死亡形式，与细胞代谢、氧化还原平衡和与癌症相关的各种信号通路有关。长链非编码 RNA（lncRNA）KB-1460A1.5 作为一种肿瘤抑制基因，调节脑胶质瘤中的肿瘤生长，但它的分子网络调控机制尚不清楚。在本研究中，我们发现 KB-1460A1.5 可以诱导脑胶质瘤发生铁死亡，并增强对铁死亡诱导剂 RSL3 的敏感性。串联质量标签蛋白质组学和非靶向代谢组学表明，KB-1460A1.5 影响多不饱和脂肪酸代谢过程。基于气相色谱-质谱的中长链脂肪酸靶向代谢组学证实，上调 KB-1460A1.5 降低了脑胶质瘤细胞中单不饱和脂肪酸、油酸（OA）和棕榈油酸（PO）的水平。OA 和 PO 的添加恢复了 KB-1460A1.5 诱导的细胞铁死亡。分子水平上，KB-1460A1.5 抑制哺乳动物雷帕霉素靶蛋白信号通路，抑制下游固醇调节元件结合蛋白 1（SREBP-1）的表达，从而减弱多不饱和脂肪酸的硬脂酰辅酶 A 去饱和酶-1（SCD1）介导的去饱和作用。最后，皮下脑胶质瘤动物模型证实，KB-1460A1.5 可以抑制肿瘤进展、SREBP-1/SCD1 表达和铁死亡。总之，在脑胶质瘤中增加 KB-1460A1.5 的表达水平可以通过 SREBP-1/SCD1 介导的脂肪生成促进癌细胞中氧化应激和铁死亡的诱导，在临床前模型中显示出治疗潜力。
