Ferroptotic cell death and cancer Cell death can occur through different mechanisms, several of which are being explored as potential targets for cancer treatment. One form of cell death that has attracted recent interest is ferroptosis, which is triggered by high intracellular levels of lipid reactive oxygen species. Pancreatic cancer cells have high levels of reactive oxygen species but manage to avoid ferroptosis by importing extracellular cysteine. Studying mice bearing pancreatic tumors, Badgley et al. found that administration of a drug inhibiting cysteine import induced tumor-selective ferroptosis and inhibited tumor growth. Further work will be required to determine whether this therapeutic strategy will be effective in human pancreatic cancer, a tumor type for which new treatments are urgently needed. Science, this issue p. 85 A drug that lowers intracellular cysteine levels inhibits growth of pancreatic tumors in mice by inducing a specific form of cell death. Ferroptosis is a form of cell death that results 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 that are derived from the amino acid cysteine. In this work, we show that the import of oxidized cysteine (cystine) via system xC– is a critical dependency of pancreatic ductal adenocarcinoma (PDAC), which is a leading cause of cancer mortality. PDAC cells used cysteine to synthesize glutathione and coenzyme A, which, together, down-regulated ferroptosis. Studying genetically engineered mice, we found that the deletion of a system xC– subunit, Slc7a11, induced tumor-selective ferroptosis and inhibited PDAC growth. This was replicated through the administration of cyst(e)inase, a drug that depletes cysteine and cystine, demonstrating a translatable means to induce ferroptosis in PDAC.

中文翻译：

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半胱氨酸耗竭诱导小鼠胰腺肿瘤铁死亡

Ferroptotic 细胞死亡和癌症 细胞死亡可以通过不同的机制发生，其中一些正在探索作为癌症治疗的潜在目标。最近引起人们兴趣的一种细胞死亡形式是铁死亡，它是由细胞内高水平的脂质活性氧引发的。胰腺癌细胞具有高水平的活性氧，但通过导入细胞外半胱氨酸来避免铁死亡。Badgley 等人研究了患有胰腺肿瘤的小鼠。发现给予抑制半胱氨酸输入的药物会诱导肿瘤选择性铁死亡并抑制肿瘤生长。需要进一步的工作来确定这种治疗策略是否对人类胰腺癌有效，这是一种迫切需要新疗法的肿瘤类型。科学，这个问题 p。85 一种降低细胞内半胱氨酸水平的药物通过诱导特定形式的细胞死亡来抑制小鼠胰腺肿瘤的生长。铁死亡是一种细胞死亡形式，由脂质活性氧 (ROS) 的灾难性积累引起。致癌信号可提高许多肿瘤类型中脂质 ROS 的产生，并被源自氨基酸半胱氨酸的代谢物抵消。在这项工作中，我们表明通过系统 xC– 导入氧化半胱氨酸（胱氨酸）是胰腺导管腺癌 (PDAC) 的关键依赖性，这是癌症死亡的主要原因。PDAC 细胞使用半胱氨酸合成谷胱甘肽和辅酶 A，它们共同下调铁死亡。研究基因工程小鼠，我们发现系统 xC– 亚基 Slc7a11 的缺失，诱导肿瘤选择性铁死亡并抑制 PDAC 生长。这通过使用胱氨酸酶（一种消耗半胱氨酸和胱氨酸的药物）进行复制，证明了一种可翻译的方法来诱导 PDAC 中的铁死亡。