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

Aging Cell

Baomin Li²  Juan Manuel Iglesias-Pedraz²  Leng-Ying Chen²  Fei Yin³  Enrique Cadenas³  Sita Reddy¹ 

[1]Institute for Genetic Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

[2]Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

[3]Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA

关键词: aging;    DNA methylation;    molecular biology of aging;    muscle;    epigenetic;   

DOI  :  10.1111/acel.12181

来源: Wiley

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2013 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.