Journal
SCIENCE
Volume 368, Issue 6486, Pages 85-+Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aaw9872
Keywords
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Categories
Funding
- NIH/NCI Cancer Center Support Grant [P30CA013696]
- Department of Education GAANN fellowship through the University of Michigan Program in Chemical Biology
- Lustgarten Foundation for Pancreatic Cancer Research
- NIH/NCI [R35 CA197687]
- Pancreatic Cancer Action Network/AACR Pathway to Leadership award [13-70-25-LYSS]
- Dale F. Frey Award for Breakthrough Scientists from the Damon Runyon Cancer Research Foundation [DFS-09-14]
- V Foundation for Cancer Research [V2016-009]
- Kimmel Scholar Award from the Sidney Kimmel Foundation for Cancer Research [SKF-16-005]
- NIH [U24-DK097153]
- PRCRP Horizon award by the Department of Defense [W81XWH-17-1-0497]
- NCI CCSG [CA014195]
- Waitt Foundation
- NCI/NIH [R35 CA197687, R35CA209896, P01CA087497]
- Cancer Center Core Grant [CA014195]
- Freeberg Foundation
- Hirschberg Foundation
- Salk Women and Special Science Award
- [T32 A009503]
- [F31 CA180738]
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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 x(C)(-) 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 x(C)(-) 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.
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