Open AccessDownregulation of the W erner syndrome protein induces a metabolic shift that compromises redox homeostasis and limits proliferation of cancer cells
Author(s) -
Li Baomin,
IglesiasPedraz Juan Manuel,
Chen LengYing,
Yin Fei,
Cadenas Enrique,
Reddy Sita,
Comai Lucio
Publication year - 2014
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.12181
Subject(s) - warburg effect , biology , cell growth , senescence , downregulation and upregulation , cancer cell , microbiology and biotechnology , gene knockdown , werner syndrome , oxidative stress , premature aging , oxidative phosphorylation , cancer , cell culture , genetics , biochemistry , gene , rna , helicase
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.