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

Baomin Li, Juan Manuel Iglesias-Pedraz, Leng Ying Chen, Fei Yin, Enrique Cadenas, Sita Reddy, Lucio Comai

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)367-378
Number of pages12
JournalAging Cell
Volume13
Issue number2
DOIs
StatePublished - Apr 2014
Externally publishedYes

Keywords

  • Aging
  • DNA methylation
  • Epigenetic
  • Molecular biology of aging
  • Muscle

ASJC Scopus subject areas

  • Aging
  • Cell Biology

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