Downregulation of the Werner syndrome protein induces a metabolic shift that compromises redox homeostasis and limits proliferation of cancer cells
Article first published online: 1 DEC 2013
© 2013 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Volume 13, Issue 2, pages 367–378, April 2014
How to Cite
Li, B., Iglesias-Pedraz, J. M., Chen, L.-Y., Yin, F., Cadenas, E., Reddy, S. and Comai, L. (2014), Downregulation of the Werner syndrome protein induces a metabolic shift that compromises redox homeostasis and limits proliferation of cancer cells. Aging Cell, 13: 367–378. doi: 10.1111/acel.12181
- Issue published online: 11 MAR 2014
- Article first published online: 1 DEC 2013
- Manuscript Accepted: 24 OCT 2013
- NIH. Grant Number: R01AG034156
- Research Facilities Improvement Program. Grant Numbers: C06 RR014514-01, C06 RR10600-01, C06 CA62528
- National Center for Research Resources
- National Institutes of Health
- DNA methylation;
- molecular biology of aging;
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.