Lysosomal cystine governs ferroptosis sensitivity in cancer via cysteine stress response.
Lysosomal cystine governs ferroptosis sensitivity in cancer via cysteine stress response.
复制标题
溶酶体胱氨酸通过半胱氨酸应激反应控制癌症中的铁死亡敏感性。
DOI：
10.1016/j.molcel.2023.08.004
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发表时间：
2023
期刊：
影响因子：
16
通讯作者：
Qian,Shu-Bing
中科院分区：
文献类型：
--
作者：
Swanda,RobertV;Ji,Quanquan;Wu,Xincheng;Yan,Jingyue;Dong,Leiming;Mao,Yuanhui;Uematsu,Saori;Dong,Yizhou;Qian,Shu-Bing
氨基酸半胱氨酸及其氧化二聚体形式胱氨酸通常被认为是代谢功能的同义词。囊肿(e)线耗竭不仅诱导氨基酸反应，而且还引发铁下垂，一种非凋亡细胞死亡。在这里，我们报道，与一般氨基酸饥饿不同，囊肿(e)氨酸剥夺在转录水平上触发ATF4诱导。出乎意料的是，引起适应性ATF4反应的是溶酶体半胱氨酸的缺乏，而不是胞质半胱氨酸的缺乏。溶酶体-核信号通路涉及芳烃受体（AhR），它通过犬尿氨酸途径感知溶酶体胱氨酸。阻断溶酶体胱氨酸外排可减弱ATF4诱导并使铁下垂增敏。为了加强癌症中的铁凋亡，我们开发了一种合成的mRNA试剂CysRx，它可以将胞质半胱氨酸转化为溶酶体半胱氨酸。cyysrx能最大限度地使癌细胞下垂，有效地抑制肿瘤在体内的生长。因此，细胞内营养重编程有可能在没有系统饥饿的情况下诱导癌症选择性铁凋亡。
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 growthin vivo. Thus, intracellular nutrient reprogramming has the potential to induce selective ferroptosis in cancer without systematic starvation.