“Cysteine depletion induces pancreatic tumor ferroptosis in mice”

作者：Michael A. Badgley, Daniel M. Kremer, H. C. Maurer, Kathleen E. DelGiorno, Ho-Joon Lee, V. Purohit, Irina Sagalovskiy, Alice Ma, Jonathan Kapilian, Christina E. M. Firl, Amanda R. Decker, Stephen A. Sastra, Carmine F. Palermo, Leonardo R Andrade, Peter Sajjakulnukit, Li Zhang, Zachary P. Tolstyka, Tal Hirschhorn, Candice Lamb, Tong Liu, W. Gu, E. S. Seeley, Everett M Stone, G. Georgiou, U. Manor, A. Iuga, G. Wahl, B. Stockwell, C. Lyssiotis, K. Olive · 发表于：Science · 年份：2020 · DOI：10.1126/science.aaw9872 · 被引用次数：1120 · 研究领域：Medicine、Chemistry

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 g...