生物
胱氨酸
细胞生物学
战斗或逃跑反应
灵敏度(控制系统)
半胱氨酸
生物化学
氧化应激
癌症研究
酶
电子工程
基因
工程类
作者
Robert V. Swanda,Quanquan Ji,Xincheng Wu,Jinyue Yan,L. Dong,Yuanhui Mao,Saori Uematsu,Yizhou Dong,Shu‐Bing Qian
出处
期刊:Molecular Cell
[Elsevier]
日期:2023-08-29
卷期号:83 (18): 3347-3359.e9
被引量:43
标识
DOI:10.1016/j.molcel.2023.08.004
摘要
Summary
The amino acid cysteine and its oxidized dimeric form cystine are commonly believed to be synonymous in metabolic functions. Cyst(e)ine depletion not only induces amino acid response but also triggers ferroptosis, a non-apoptotic cell death. Here, we report that unlike general amino acid starvation, cyst(e)ine deprivation triggers ATF4 induction at the transcriptional level. Unexpectedly, it is the shortage of lysosomal cystine, but not the cytosolic cysteine, that elicits the adaptative ATF4 response. The lysosome-nucleus signaling pathway involves the aryl hydrocarbon receptor (AhR) that senses lysosomal cystine via the kynurenine pathway. A blockade of lysosomal cystine efflux attenuates ATF4 induction and sensitizes ferroptosis. To potentiate ferroptosis in cancer, we develop a synthetic mRNA reagent, CysRx, that converts cytosolic cysteine to lysosomal cystine. CysRx maximizes cancer cell ferroptosis and effectively suppresses tumor growth in vivo. Thus, intracellular nutrient reprogramming has the potential to induce selective ferroptosis in cancer without systematic starvation.
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