Downregulation of the Werner syndrome protein induces a metabolic shift that compromises redox homeostasis and limits proliferation of cancer cells.
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.
Baomin
B
Li
Juan Manuel
JM
Iglesias-Pedraz
Leng-Ying
LY
Chen
Fei
F
Yin
Enrique
E
Cadenas
Sita
S
Reddy
Lucio
L
Comai
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019069:Cell Respiration / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects; D004249:DNA Damage; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics*; D004734:Energy Metabolism / Q000187:drug effects; D005090:Exodeoxyribonucleases / Q000235:genetics* / Q000378:metabolism; D055785:Gene Knockdown Techniques; D005978:Glutathione / Q000378:metabolism / Q000494:pharmacology; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D046911:Macromolecular Substances / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D009536:Niacinamide / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D053484:RecQ Helicases / Q000235:genetics* / Q000378:metabolism; D014898:Werner Syndrome / Q000235:genetics; D000071657:Werner Syndrome Helicase
D000975:Antioxidants; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D046911:Macromolecular Substances; D017382:Reactive Oxygen Species; D009536:Niacinamide; D005090:Exodeoxyribonucleases; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase; D005978:Glutathione