Abstract：
: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 (SLC7A11high) 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 SLC7A11high 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 SLC7A11high cancer cells and suppress SLC7A11high 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 SLC7A11high cancers.
journal_name
Nat Cell Bioljournal_title
Nature cell biologyauthors
Liu X,Olszewski K,Zhang Y,Lim EW,Shi J,Zhang X,Zhang J,Lee H,Koppula P,Lei G,Zhuang L,You MJ,Fang B,Li W,Metallo CM,Poyurovsky MV,Gan Bdoi
10.1038/s41556-020-0496-xsubject
Has Abstractpub_date
2020-04-01 00:00:00pages
476-486issue
4eissn
1465-7392issn
1476-4679pii
10.1038/s41556-020-0496-xjournal_volume
22pub_type
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