MYCN 上调转硫化途径,抑制 MYCN 扩增的神经母细胞瘤的铁质易损性。

IF 4.1 Q2 CELL BIOLOGY Cell Stress Pub Date : 2022-01-17 eCollection Date: 2022-02-01 DOI:10.15698/cst2022.02.264
Konstantinos V Floros, Ayesha T Chawla, Mia O Johnson-Berro, Rishabh Khatri, Angeliki M Stamatouli, Sosipatros A Boikos, Mikhail G Dozmorov, L Ashley Cowart, Anthony C Faber
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引用次数: 0

摘要

铁变态反应是一种依赖铁的氧化性细胞死亡形式,主要通过谷胱甘肽过氧化物酶 4(GPX4)和由半胱氨酸生成的谷胱甘肽(GSH)来对抗。目前刚刚发现哪些癌症可从药理铁诱导中获益。我们最近证明,通过基因或药物诱导 MYCN 扩增的神经母细胞瘤(NB)中的铁变态反应是杀死这些细胞的一种新颖而有效的方法。MYCN 通过增加转铁蛋白受体 1(TfR1)的表达和降低铁蛋白受体的水平,增加了铁代谢和随后的羟自由基。为了对抗增加的羟自由基,MYCN 与 SLC3A2(溶质运载家族 3 成员 2)的启动子结合。SLC3A2 是半胱氨酸-谷氨酸反转运体 Xc- 系统的一个亚基,该系统输出谷氨酸,输入胱氨酸。胱氨酸在细胞内转化为半胱氨酸。在此,我们研究了 MYCN 增加半胱氨酸水平的其他途径。通过在表达 MYCN 或 GFP 的合成 NB 细胞系中进行代谢组学研究,我们证明 MYCN 激活了转硫化途径。此外,我们还证明 MYCN 扩增的 NB 细胞系和肿瘤具有更高水平的胱硫醚 beta 合成酶(CBS),它是转硫化过程中的限速酶,会导致硫醚胱硫醚(R-S-(2-氨基-2-羧基乙基)-l-高半胱氨酸)水平升高。此外,MYCN 扩增的 NB 肿瘤具有较高水平的甲硫腺苷磷酸化酶(MTAP),这种酶有助于在多胺代谢后挽救蛋氨酸。MYCN 直接与 MTAP 的启动子结合。我们提出,MYCN 可协调胱氨酸摄取的增强和转硫化途径活性的增强,以抵消铁诱导的芬顿反应所产生的活性氧(ROS)的增加,最终导致 MYCN 扩增的神经母细胞瘤铁变态反应的脆弱性。
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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MYCN upregulates the transsulfuration pathway to suppress the ferroptotic vulnerability in MYCN-amplified neuroblastoma.

Ferroptosis is an iron-dependent, oxidative form of cell death that is countered mainly by glutathione peroxidase 4 (GPX4) and the production of glutathione (GSH), which is formed from cysteine. The identification of the cancers that may benefit from pharmacological ferroptotic induction is just emerging. We recently demonstrated that inducing ferroptosis genetically or pharmacologically in MYCN-amplified neuroblastoma (NB) is a novel and effective way to kill these cells. MYCN increases iron metabolism and subsequent hydroxyl radicals through increased expression of the transferrin receptor 1 (TfR1) and low levels of the ferroportin receptor. To counter increased hydroxyl radicals, MYCN binds to the promoter of SLC3A2 (solute carrier family 3 member 2). SLC3A2 is a subunit of system Xc-, which is the cysteine-glutamate antiporter that exports glutamate and imports cystine. Cystine is converted to cysteine intracellularly. Here, we investigated other ways MYCN may increase cysteine levels. By performing metabolomics in a syngeneic NB cell line either expressing MYCN or GFP, we demonstrate that the transsulfuration pathway is activated by MYCN. Furthermore, we demonstrate that MYCN-amplified NB cell lines and tumors have higher levels of cystathionine beta-synthase (CBS), the rate-limiting enzyme in transsulfuration, which leads to higher levels of the thioether cystathionine (R-S-(2-amino-2-carboxyethyl)-l-homocysteine). In addition, MYCN-amplified NB tumors have high levels of methylthioadenosine phosphorylase (MTAP), an enzyme that helps salvage methionine following polyamine metabolism. MYCN directly binds to the promoter of MTAP. We propose that MYCN orchestrates both enhanced cystine uptake and enhanced activity of the transsulfuration pathway to counteract increased reactive oxygen species (ROS) from iron-induced Fenton reactions, ultimately contributing to a ferroptosis vulnerability in MYCN-amplified neuroblastoma.

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来源期刊
Cell Stress
Cell Stress Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (miscellaneous)
CiteScore
13.50
自引率
0.00%
发文量
21
审稿时长
15 weeks
期刊介绍: Cell Stress is an open-access, peer-reviewed journal that is dedicated to publishing highly relevant research in the field of cellular pathology. The journal focuses on advancing our understanding of the molecular, mechanistic, phenotypic, and other critical aspects that underpin cellular dysfunction and disease. It specifically aims to foster cell biology research that is applicable to a range of significant human diseases, including neurodegenerative disorders, myopathies, mitochondriopathies, infectious diseases, cancer, and pathological aging. The scope of Cell Stress is broad, welcoming submissions that represent a spectrum of research from fundamental to translational and clinical studies. The journal is a valuable resource for scientists, educators, and policymakers worldwide, as well as for any individual with an interest in cellular pathology. It serves as a platform for the dissemination of research findings that are instrumental in the investigation, classification, diagnosis, and therapeutic management of major diseases. By being open-access, Cell Stress ensures that its content is freely available to a global audience, thereby promoting international scientific collaboration and accelerating the exchange of knowledge within the research community.
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