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

https://doi.org/10.1016/j.freeradbiomed.2010.12.038Get rights and content

Abstract

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.

Section snippets

Materials

Modified Eagle medium with Earl salts, l-glutamine, and sodium bicarbonate; Dulbecco's modified Eagle medium with high glucose, l-glutamine, and sodium bicarbonate; and Dulbecco's modified Eagle medium:nutrient mixture F-12 were obtained from Sigma–Aldrich (St. Louis, MO, USA). Penicillin/streptomycin, nonessential amino acids, and fetal bovine serum were obtained from Hyclone (Logan, UT, USA). Resveratrol was obtained from A.G. Scientific (San Diego, CA, USA). Sirtinol and diarylpropionitrile

Results

Many of RES's reported effects are consistent with an increase in cellular stress resistance [1]. To investigate the long-term effects of RES on stress resistance we incubated three mammalian cell lines with RES for 48 h, and removed it before exposure to the oxidizing agents hydrogen peroxide and paraquat and the methylating agent methylmethanesulfonate (MMS). Pretreatment with RES significantly increased resistance to hydrogen peroxide and paraquat in all three cell lines. Similarly, a

Discussion

Two of RES's most exciting effects in the context of human health are its abilities to protect cells against stress-induced death and to slow rates of proliferative cell growth. Here we have shown that both of these effects are concurrent with, and dependent upon, the ability of RES to increase protein levels and activity of MnSOD. This observation is particularly interesting given the importance of MnSOD. In many cell types, mitochondria are the primary producer of intracellular reactive

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