Differential prooxidative effects of the green tea polyphenol, (-)-epigallocatechin-3-gallate, in normal and oral cancer cells are related to differences in sirtuin 3 signaling

Mol Nutr Food Res. 2015 Feb;59(2):203-11. doi: 10.1002/mnfr.201400485. Epub 2014 Nov 17.

Abstract

Scope: We have previously reported that the green tea catechin, (-)-epigallocatechin-3-gallate (EGCG), can induce oxidative stress in oral cancer cells but exerts antioxidant effects in normal cells. Here, we report that these differential prooxidative effects are associated with sirtuin 3 (SIRT3), an important mitochondrial redox modulator.

Methods and results: EGCG rapidly induced mitochondria-localized reactive oxygen species in human oral squamous carcinoma cells (SCC-25, SCC-9) and premalignant leukoplakia cells (MSK-Leuk1), but not in normal human gingival fibroblast cells (HGF-1). EGCG suppressed SIRT3 mRNA and protein expression, as well as, SIRT3 activity in SCC-25 cells, whereas it increased SIRT3 activity in HGF-1 cells. EGCG selectively decreased the nuclear localization of the estrogen-related receptor α (ERRα), the transcription factor regulating SIRT3 expression, in SCC-25 cells. This indicates that EGCG may regulate SIRT3 transcription in oral cancer cells via ERRα. EGCG also differentially modulated the mRNA expressions of SIRT3-associated downstream targets including glutathione peroxidase 1 and superoxide dismutase 2 in normal and oral cancer cells.

Conclusion: SIRT3 represents a novel potential target through which EGCG exerts differential prooxidant effects in cancer and normal cells. Our results provide new biomarkers to be further explored in animal studies.

Keywords: (-)-Epigallocatechin-3-gallate; Oral cancer; Prooxidant effects; Sirtuin 3; Tea.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antioxidants / pharmacology
  • Catechin / analogs & derivatives*
  • Catechin / pharmacology
  • Cell Line, Tumor
  • Gene Expression Regulation
  • Glutathione Peroxidase / genetics
  • Glutathione Peroxidase / metabolism
  • Humans
  • Mitochondria
  • Mouth Neoplasms / drug therapy
  • Oxidative Stress / drug effects
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Polyphenols / pharmacology*
  • Reactive Oxygen Species / metabolism
  • Receptors, Estrogen / genetics
  • Receptors, Estrogen / metabolism
  • Signal Transduction
  • Sirtuin 3 / genetics
  • Sirtuin 3 / metabolism*
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase / metabolism
  • Tea / chemistry*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism

Substances

  • Antioxidants
  • ERRalpha estrogen-related receptor
  • PPARGC1A protein, human
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Polyphenols
  • Reactive Oxygen Species
  • Receptors, Estrogen
  • Tea
  • Transcription Factors
  • Catechin
  • epigallocatechin gallate
  • glutathione peroxidase GPX1
  • Glutathione Peroxidase
  • Superoxide Dismutase
  • superoxide dismutase 2
  • Sirtuin 3