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

[werner syndrome]

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 .