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Banjac, A. ; Perisic, T. ; Sato, H.* ; Seiler, A. ; Bannai, S.* ; Weiss, N.* ; Kölle, P.* ; Tschoep, K.* ; Issels, R.D.* ; Daniel, PT.* ; Conrad, M. ; Bornkamm, G.W.

The cystine/cysteine cycle: A redox cycle regulating susceptibility versus resistance to cell death.

Oncogene 27, 1618-1628 (2008)
DOI
Open Access Green as soon as Postprint is submitted to ZB.
The glutathione-dependent system is one of the key systems regulating cellular redox balance, and thus cell fate. Cysteine, typically present in its oxidized form cystine in the extracellular space, is regarded as the rate-limiting substrate for glutathione (GSH) synthesis. Cystine is transported into cells by the highly specific amino-acid antiporter system xc-. Since Burkitt's Lymphoma (BL) cells display limited uptake capacity for cystine, and are thus prone to oxidative stress-induced cell death, we stably expressed the substrate-specific subunit of system xc-, xCT, in HH514 BL cells. xCT-overexpressing cells became highly resistant to oxidative stress, particularly upon GSH depletion. Contrary to previous predictions, the increase of intracellular cysteine did not affect the cellular GSH pool, but concomitantly boosted extracellular cysteine concentrations. Even though cells were depleted of bulk GSH, xCT overexpression maintained cellular integrity by protecting against lipid peroxidation, a very early event in cell death progression. Our results show that system xc- protects against oxidative stress not by elevating intracellular GSH levels, but rather creates a reducing extracellular environment by driving a highly efficient cystine/cysteine redox cycle. Our findings show that the cystine/cysteine redox cycle by itself must be viewed as a discrete major regulator of cell survival.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords cystine-glutamate exchange; glutathione metabolism; lipid peroxidation; redox regulation; system xc
ISSN (print) / ISBN 0950-9232
e-ISSN 0950-9232
Journal Oncogene
Quellenangaben Volume: 27, Issue: 11, Pages: 1618-1628 Article Number: , Supplement: ,
Publisher Nature Publishing Group
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Clinical Molecular Biology and Tumor Genetics (K.MOLBI)
CCG Tumor Therapy with Hyperthermia (IMI-KTH)