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Stress-induced inhibition of nonsense-mediated RNA decay regulates intracellular cystine transport and intracellular glutathione through regulation of the cystine/glutamate exchanger SLC7A11

Oncogene volume 34, pages 4211–4218 (2015)Cite this article

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Abstract

SLC7A11 encodes a subunit of the xCT cystine/glutamate amino-acid transport system and has a critical role in the generation of glutathione and the protection of cells from oxidative stress. Expression of SLC7A11 promotes tumorigenesis and chemotherapy resistance, but while SLC7A11 has been previously noted to be upregulated in hypoxic cells, its regulation has not been fully delineated. We have recently shown that nonsense-mediated RNA decay (NMD) is inhibited by cellular stresses generated by the tumor microenvironment, including hypoxia, and augments tumorigenesis. Here we demonstrate that the inhibition of NMD by various cellular stresses leads to the stabilization and upregulation of SLC7A11 mRNA and protein. The inhibition of NMD and upregulation of SLC7A11 augments intracellular cystine transport and increases intracellular levels of cysteine and glutathione. Accordingly, the inhibition of NMD protects cells against oxidative stress via SLC7A11 upregulation. Together our studies identify a mechanism for the dynamic regulation of SLC7A11, through the stress-inhibited regulation of NMD, and add to the growing evidence that the inhibition of NMD is an adaptive response.

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Acknowledgements

This work was supported by RO1DK081641 (to LBG), a generous gift from Mr Arthur Levine and Ms Diane Lederman and the NYU Cancer Institute. LBG was the Saul Farber Associate Professor of Medicine.

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Authors and Affiliations

  1. Department of Medicine, New York University School of Medicine, New York, NY, USA

    L Martin & L B Gardner

  2. Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY, USA

    L B Gardner

  3. NYU Perlmutter Cancer Center, New York University School of Medicine, New York, NY, USA

    L B Gardner

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  1. L Martin
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  2. L B Gardner
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Correspondence to L B Gardner.

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Martin, L., Gardner, L. Stress-induced inhibition of nonsense-mediated RNA decay regulates intracellular cystine transport and intracellular glutathione through regulation of the cystine/glutamate exchanger SLC7A11. Oncogene 34, 4211–4218 (2015). https://doi.org/10.1038/onc.2014.352

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