Downregulation of the Werner syndrome protein induces a metabolic shift that compromises redox homeostasis and limits proliferation of cancer cells

Authors

  • Baomin Li,

    1. Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
    2. Institute for Genetic Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
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  • Juan Manuel Iglesias-Pedraz,

    1. Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
    2. Institute for Genetic Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
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  • Leng-Ying Chen,

    1. Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
    2. Institute for Genetic Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
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  • Fei Yin,

    1. Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA
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  • Enrique Cadenas,

    1. Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA
    2. Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
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  • Sita Reddy,

    1. Institute for Genetic Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
    2. Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
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  • Lucio Comai

    Corresponding author
    1. Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
    2. Institute for Genetic Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
    • Correspondence

      Lucio Comai, Keck School of Medicine of USC, 2250 Alcazar Street, CSC 264, Los Angeles, CA 90033, USA. Tel.: +1(323) 442-3950; fax: +1(323) 442-2764; e-mail: comai@med.usc.edu

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Summary

The Werner syndrome protein (WRN) is a nuclear protein required for cell growth and proliferation. Loss-of-function mutations in the Werner syndrome gene are associated with the premature onset of age-related diseases. How loss of WRN limits cell proliferation and induces replicative senescence is poorly understood. Here, we show that WRN depletion leads to a striking metabolic shift that coordinately weakens the pathways that generate reducing equivalents for detoxification of reactive oxygen species and increases mitochondrial respiration. In cancer cells, this metabolic shift counteracts the Warburg effect, a defining characteristic of many malignant cells, resulting in altered redox balance and accumulation of oxidative DNA damage that inhibits cell proliferation and induces a senescence-like phenotype. Consistent with these findings, supplementation with antioxidant rescues at least in part cell proliferation and decreases senescence in WRN-knockdown cancer cells. These results demonstrate that WRN plays a critical role in cancer cell proliferation by contributing to the Warburg effect and preventing metabolic stress.

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