Long non-coding RNA KB-1460A1.5 promotes ferroptosis by inhibiting mTOR/SREBP-1/SCD1-mediated polyunsaturated fatty acid desaturation in glioma.

IF 3.3 3区 医学 Q2 ONCOLOGY
Lixia Xu, Binli Wen, Qiaoli Wu, Shan Lu, Jianwen Liao, Lidong Mo, Qingguo Li, Xiaoguang Tong, Hua Yan
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引用次数: 0

Abstract

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.

长非编码RNA KB-1460A1.5通过抑制胶质瘤中mTOR/SREBP-1/SCD1介导的多不饱和脂肪酸脱饱和来促进铁变态反应。
铁氧化是一种新的细胞调节性死亡形式,由磷脂的铁依赖性过氧化引起,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。长非编码 RNA(lncRNA)KB-1460A1.5 作为抑癌基因调控胶质瘤的肿瘤生长,但其分子网络调控机制尚不清楚。本研究发现,KB-1460A1.5能诱导胶质瘤的铁突变,并提高胶质瘤对铁突变诱导剂RSL3的敏感性。TMT蛋白质组学和非靶向代谢组学表明,KB-1460A1.5会影响多不饱和脂肪酸的代谢过程。基于 GC-MS 的中链和长链脂肪酸靶向代谢组学证实,上调 KB-1460A1.5 会降低胶质瘤细胞中单不饱和脂肪酸 (MUFA)、油酸 (OA) 和棕榈油酸 (PO) 的水平。加入油酸和棕榈油酸后,KB-1460A1.5 诱导的细胞铁变态反应得以恢复。分子方面,KB-1460A1.5 可抑制 mTOR 信号通路,从而抑制下游固醇调节元件结合蛋白 1(SREBP-1)的表达,从而减弱硬脂酰-CoA 去饱和酶-1(SCD1)介导的多不饱和脂肪酸的去饱和作用。最后,皮下胶质瘤动物模型证实,KB-1460A1.5 可抑制肿瘤进展、SREBP1/SCD1 的表达和铁变态反应。总之,提高KB-1460A1.5在胶质瘤中的表达水平可通过SREBP1/SCD1介导的脂肪生成,促进诱导癌细胞的氧化应激和铁变态反应,在临床前模型中显示出治疗潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Carcinogenesis
Carcinogenesis 医学-肿瘤学
CiteScore
9.20
自引率
2.10%
发文量
95
审稿时长
1 months
期刊介绍: Carcinogenesis: Integrative Cancer Research is a multi-disciplinary journal that brings together all the varied aspects of research that will ultimately lead to the prevention of cancer in man. The journal publishes papers that warrant prompt publication in the areas of Biology, Genetics and Epigenetics (including the processes of promotion, progression, signal transduction, apoptosis, genomic instability, growth factors, cell and molecular biology, mutation, DNA repair, genetics, etc.), Cancer Biomarkers and Molecular Epidemiology (including genetic predisposition to cancer, and epidemiology), Inflammation, Microenvironment and Prevention (including molecular dosimetry, chemoprevention, nutrition and cancer, etc.), and Carcinogenesis (including oncogenes and tumor suppressor genes in carcinogenesis, therapy resistance of solid tumors, cancer mouse models, apoptosis and senescence, novel therapeutic targets and cancer drugs).
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