期刊
NATURE CELL BIOLOGY
卷 22, 期 4, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41556-020-0496-x
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资金
- Andrew Sabin Family Fellow Award from The University of Texas MD Anderson Cancer Center
- Bridge Fund from The University of Texas MD Anderson Cancer Center
- Career Enhancement Award from University of Texas Specialized Program of Research Excellence in Lung Cancer National Institutes of Health/National Cancer Institute [5P50CA070907]
- Department of Defense Kidney Cancer Research Program [KC180131]
- National Institutes of Health [R01CA181196, R01CA188652]
- CPRIT Research Training Grant [RP170067]
- Dr. John J. Kopchick Research Award from The MD Anderson UTHealth Graduate School of Biomedical Sciences
- National Institutes of Health grant [T32EB009380]
- University of Texas MD Anderson Cancer Center Moon Shots Program
- Specialized Program of Research Excellence grant [CA070907]
- University of Texas PDX Development and Trial Center grant [U54CA224065]
- National Institutes of Health Cancer Center Support Grant [P30CA016672]
- CDMRP [KC180131, 1102364] Funding Source: Federal RePORTER
SLC7A11-mediated cystine uptake is critical for maintaining redox balance and cell survival. Here we show that this comes at a significant cost for cancer cells with high levels of SLC7A11. Actively importing cystine is potentially toxic due to its low solubility, forcing cancer cells with high levels of SLC7A11 (SLC7A11(high)) to constitutively reduce cystine to the more soluble cysteine. This presents a significant drain on the cellular NADPH pool and renders such cells dependent on the pentose phosphate pathway. Limiting glucose supply to SLC7A11(high) cancer cells results in marked accumulation of intracellular cystine, redox system collapse and rapid cell death, which can be rescued by treatments that prevent disulfide accumulation. We further show that inhibitors of glucose transporters selectively kill SLC7A11(high) cancer cells and suppress SLC7A11(high) tumour growth. Our results identify a coupling between SLC7A11-associated cystine metabolism and the pentose phosphate pathway, and uncover an accompanying metabolic vulnerability for therapeutic targeting in SLC7A11(high) cancers. Liu et al. show that cancer cells with high levels of SLC7A11 have increased dependency on the pentose phosphate pathway and consequently accumulate disulfide, and can be therapeutically targeted by limiting glucose supply.
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