Cysteine depletion induces pancreatic tumor ferroptosis in mice.
Cysteine depletion induces pancreatic tumor ferroptosis in mice.
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DOI：
10.1126/science.aaw9872
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发表时间：
2020-04-03
期刊：
影响因子：
--
通讯作者：
Olive KP
中科院分区：
文献类型：
--
作者：
Badgley MA;Kremer DM;Maurer HC;DelGiorno KE;Lee HJ;Purohit V;Sagalovskiy IR;Ma A;Kapilian J;Firl CEM;Decker AR;Sastra SA;Palermo CF;Andrade LR;Sajjakulnukit P;Zhang L;Tolstyka ZP;Hirschhorn T;Lamb C;Liu T;Gu W;Seeley ES;Stone E;Georgiou G;Manor U;Iuga A;Wahl GM;Stockwell BR;Lyssiotis CA;Olive KP
铁凋亡是由脂质活性氧（ROS）的灾难性积累引起的细胞死亡的一种形式。致癌信号在许多肿瘤类型中升高脂质ROS的产生，并且被来自氨基酸半胱氨酸的代谢物抵消。在这里，我们表明，通过系统xC-氧化半胱氨酸（胱氨酸）的进口是胰腺导管腺癌（PDAC），癌症死亡率的主要原因的关键依赖。利用半胱氨酸合成谷胱甘肽和辅酶A，二者结合控制铁凋亡。研究基因工程小鼠，我们发现缺失系统xC-亚基Slc 7a 11可诱导肿瘤选择性铁凋亡并抑制PDAC生长。这是通过给予半胱氨酸酶（一种消耗半胱氨酸/胱氨酸的药物）复制的，证明了诱导PDAC中铁凋亡的可转化方法。胱氨酸输入的遗传和药理学靶向诱导基因工程小鼠胰腺肿瘤中的癌症选择性铁凋亡。
Ferroptosis is a form of cell death resulting from the catastrophic accumulation of lipid reactive oxygen species (ROS). Oncogenic signaling elevates lipid ROS production in many tumor types and is counteracted by metabolites derived from the amino acid cysteine. Here we show that the import of oxidized cysteine (cystine) via system xC– is a critical dependency of pancreatic ductal adenocarcinoma (PDAC), a leading cause of cancer mortality. Cysteine was used to synthesize glutathione and coenzyme A which combined to control ferroptosis. Studying genetically engineered mice, we found that deletion of a system xC– subunit, Slc7a11, induced tumor-selective ferroptosis and inhibited PDAC growth. This was replicated through administration of cyst(e)inase, a drug that depletes cysteine/cystine, demonstrating a translatable means to induce ferroptosis in PDAC. Genetic and pharmacological targeting of cystine import induces cancer-selective ferroptosis in pancreatic tumors of genetically engineered mice.
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影响因子：
64.5
作者：
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影响因子：
11.5
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Eberle-Singh, Jaime A.;Sagalovskiy, Irina;Olive, Kenneth P.
通讯作者：
Olive, Kenneth P.
影响因子：
21.3
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通讯作者：
Conrad M