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

Oncogene volume 27, pages 1618–1628 (2008)Cite this article

Abstract

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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Acknowledgements

We thank A Richter for expert technical assistance, A Klöpfer for technical advice and J-M Bechét for critical reading of the manuscript. We are grateful to T Schroeder for the p141CAG-3SIP vector, W Droege and A Roscher for helpful discussions. This work was supported by a grant of Deutsche Forschungsgemeinschaft (Priority Programme ‘Biology of Selenoproteins’) to GWB and MC, by a short-term fellowship of Deutsche Akademische Austauschdienst (DAAD), and Japanese Society for Promotion of Science (JSPS) to HS and MC for working in Munich and in Tsuruoka, respectively. GWB was additionally supported by Fonds der Chemischen Industrie.

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Author notes

  1. H Sato

    Present address: 6Current address: Department of Bioresources, Faculty of Agriculture, Yamagata University, Tsuruoka, Yamagata 997-8555, Japan.,

  2. M Conrad and G W Bornkamm: These authors contributed equally to this work.

Authors and Affiliations

  1. GSF-Forschungszentrum für Umwelt und Gesundheit, Institut für Klinische Molekularbiologie und Tumorgenetik, München, Germany

    A Banjac, T Perisic, A Seiler, M Conrad & G W Bornkamm

  2. Department of Biochemistry, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan

    H Sato & S Bannai

  3. Medizinische Poliklinik Innenstadt der Ludwig-Maximilians-Universität, München, Germany

    N Weiss & P Kölle

  4. Medizinische Klinik III der Ludwig-Maximilians-Universität, GSF-Klinische Kooperationsgruppe Hyperthermie, München, Germany

    K Tschoep & R D Issels

  5. Medizinische Klinik mit Schwerpunkt Hämatologie und Onkologie, Charité, Humboldt Universität, Berlin, Germany

    P T Daniel

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  1. A Banjac
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Correspondence to M Conrad.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Banjac, A., Perisic, T., Sato, H. et al. The cystine/cysteine cycle: a redox cycle regulating susceptibility versus resistance to cell death. Oncogene 27, 1618–1628 (2008). https://doi.org/10.1038/sj.onc.1210796

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