Dual Action of Sulforaphane in the Regulation of Thioredoxin Reductase and Thioredoxin in Human HepG2 and Caco-2 Cells

Abstract

We have previously demonstrated that sulforaphane is a potent inducer for thioredoxin reductase in HepG2 and MCF-7 cells (Zhang et al. Carcinogenesis 2003, 24, 497-503; Wang et al. J. Agric. Food Chem. 2005, 53, 1417-1421). In this study, we have shown that sulforaphane is not only an inducer for thioredoxin reductase but also an inducer for its substrate, thioredoxin in HepG2, and undifferentiated Caco-2 cells. Sulforaphane acts at two levels in the regulation of thioredoxin reductase/thioredoxin system by the upregulation of the expression of both the enzyme and the substrate. In human hepatoma HepG2 cells, sulforaphane induced thioredoxin reductase mRNA and protein by 4- and 2-fold, respectively, whereas thioredoxin mRNA was induced 2.9-fold and thioredoxin protein was unchanged in whole cell extracts, but an increase in nuclear accumulation (1.8-fold) was observed. Moreover, the induction of thioredoxin reductase was found faster than that of thioredoxin. The effects of PI3K and MAPK kinase inhibitors, LY294002, PD98059, SP600125, and SB202190, have been investigated on the sulforaphane-induced expression of thioredoxin reductase and thioredoxin. PD98059 abrogates the sulforaphane-induced thioredoxin reductase at both mRNA and protein levels in HepG2 cells, although other inhibitors were found less effective. However, both PD98059 and LY294002 significantly decrease thioredoxin mRNA expression in HepG2 cells. None of the inhibitors tested were able to modulate the level of expression of either thioredoxin reductase mRNA or protein in Caco-2 cells suggesting that there are cell-specific responses to sulforaphane. In summary, the dietary isothiocyanate, sulforaphane, is important in the regulation of thioredoxin reductase/thioredoxin redox system in cells.

Synergy between sulforaphane and selenium in protection against oxidative damage in colonic CCD841 cells

“…These data are consistent with previous publications on tumor cell lines such as colon cancer Caco-2 and breast cancer MCF-7 cells[34,35]. The effect of SFN and/or Se on TrxR-1 protein expression in CCD841 was determined using Western blot analysis.…”

Direct and indirect antioxidant properties of inducers of cytoprotective proteins

“…Importantly, the levels of both thioredoxin and thioredoxin reductase are transcriptionally upregulated by inducers of cytoprotective enzymes through their respective AREs [33,[41][42][43][44].…”

Mechanisms of the Anticancer Effects of Isothiocyanates

“…SFN induces Nrf2 expression by inhibition of p38 and activation of heme oxygenase 1 in hepatoma cells [131]. In addition, induction of thioredoxin reductase and inhibition of key survival and proliferation pathways such as NFκB and AP-1 contributes to the chemopreventive activity of ITCs [133,[135][136][137].…”