Resveratrol interacts with estrogen receptor-β to inhibit cell replicative growth and enhance stress resistance by upregulating mitochondrial superoxide dismutase.

trans-Resveratrol (RES) is one of a number of dietary polyphenols that have been reported to beneficially affect human physiology. Although numerous studies have attributed this to direct interactions between RES and histone deacetylases, recently the reliability of these results has been questioned. We have shown that the mitochondrial superoxide dismutase (MnSOD) is substantially upregulated in RES-treated cells. Here we explore the mechanisms underlying this, showing that two of RES's more interesting effects, inhibition of replication and enhancement of stress resistance, are mediated by MnSOD upregulation in three cell lines: MRC5 human lung fibroblasts, C2C12 mouse myoblasts, and SHSY5Y human neuroblastoma cells. When small interfering RNA was used to prevent induction of MnSOD expression, the effects of RES on population doubling time of cells in culture, and resistance to cell death after exposure to hydrogen peroxide or paraquat, were abolished. Interestingly, the RES-induced upregulation of MnSOD levels could be prevented by the estrogen receptor antagonist ICI 182780. RES's effects also could be reproduced using estradiol or the estrogen receptor-β agonist diarylpropionitrile, but not using the estrogen receptor-α agonist propylpyrazole triol. Thus, we suggest that RES interacts with estrogen receptor-β to induce the upregulation of MnSOD, which affects cell cycle progression and stress resistance. These results have important implications for our understanding of RES's biological activities and potential applications to human health.