MYCN upregulates the transsulfuration pathway to suppress the ferroptotic vulnerability in MYCN-amplified neuroblastoma.
MYCN upregulates the transsulfuration pathway to suppress the ferroptotic vulnerability in MYCN-amplified neuroblastoma.
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DOI：
10.15698/cst2022.02.264
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发表时间：
2022-03
期刊：
影响因子：
6.4
通讯作者：
Faber AC
中科院分区：
文献类型：
--
作者：
Floros KV;Chawla AT;Johnson-Berro MO;Khatri R;Stamatouli AM;Boikos SA;Dozmorov MG;Cowart LA;Faber AC
铁死亡是一种依赖铁的氧化形式的细胞死亡，主要由谷胱甘肽过氧化物酶4 （GPX4）和由半胱氨酸形成的谷胱甘肽（GSH）的产生来对抗。对可能受益于药物致铁诱导的癌症的鉴定才刚刚出现。我们最近证明，基因或药理学诱导mycn扩增的神经母细胞瘤（NB）的铁下垂是一种新的有效的杀死这些细胞的方法。MYCN通过增加转铁蛋白受体1 （TfR1）的表达和低水平的铁转运蛋白受体增加铁代谢和随后的羟基自由基。为了对抗增加的羟基自由基，MYCN与SLC3A2（溶质载体家族3成员2）的启动子结合。SLC3A2是Xc-系统的一个亚基，Xc-系统是输出谷氨酸和输入胱氨酸的半胱氨酸-谷氨酸反转运蛋白。半胱氨酸在细胞内转化为半胱氨酸。在这里，我们研究了MYCN可能增加半胱氨酸水平的其他途径。通过对表达MYCN或GFP的同源NB细胞系进行代谢组学研究，我们证明了MYCN激活了转硫途径。此外，我们证明mycn扩增的NB细胞系和肿瘤具有更高水平的半胱硫氨酸β合成酶（CBS），这是转硫的限速酶，导致更高水平的硫醚半胱硫氨酸（R-S-（2-氨基-2-羧乙基）-l-同型半胱氨酸）。此外，mycn扩增的NB肿瘤具有高水平的甲基硫腺苷磷酸化酶（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。我们认为MYCN协调了胱氨酸摄取的增强和转硫途径的增强活性，以抵消铁诱导的芬顿反应引起的活性氧（ROS）的增加，最终导致MYCN扩增的神经母细胞瘤中的铁凋亡易感。
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.
影响因子：
2.9
作者：
Guan, Rong;Ho, Meng-Chiao;Brenowitz, Michael;Tyler, Peter C.;Evans, Gary B.;Almo, Steven C.;Schramm, Vern L.
通讯作者：
Schramm, Vern L.