Journal Article

Synergy between sulforaphane and selenium in the induction of thioredoxin reductase 1 requires both transcriptional and translational modulation

Jinsong Zhang, Vanda Švehlíková, Yongping Bao, A.Forbes Howie, Geoffrey J. Beckett and Gary Williamson

in Carcinogenesis

Volume 24, issue 3, pages 497-503
Published in print March 2003 | ISSN: 0143-3334
Published online March 2003 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/24.3.497
Synergy between sulforaphane and selenium in the induction of thioredoxin reductase 1 requires both transcriptional and translational modulation

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Thioredoxin reductases (TrxRs) catalyse the NADPH-dependent reduction of thioredoxin and play an important role in multiple cellular events related to carcinogenesis including cell proliferation, apoptosis and cell signaling. We have used human hepatoma HepG2 cells to examine the regulation of TrxRs by isothiocyanate (sulforaphane) and selenium (Se). We show that TrxR1 mRNA, but not TrxR2 mRNA, is induced up to 4-fold by sulforaphane, and this increase was abolished by actinomycin D, a transcription inhibitor. Se, in the form of sodium selenite, induced TrxR1 at the translational level, as shown by an increase in protein (2.1-fold) and activity (4.8-fold), but not mRNA. In combination, sulforaphane and Se synergistically induced TrxR1 protein (5.5-fold), activity (13-fold) and mRNA (6.5-fold). Although Se does not induce TrxR1 mRNA, Se can delay the degradation of sulforaphane-induced TrxR1 mRNA. Modulation of TrxR1 mRNA by sulforaphane was glutathione and protein kinase C-dependent, as L-buthionine-S,R-sulfoximine (a specific inhibitor of glutathione synthesis), and the protein kinase C inhibitor 1-(5-isoquinolinesulfonyl)-2-methyl-piperazine, significantly reduced the induction. The combination of sulforaphane and Se also efficiently protected HepG2 cells from paraquat-induced cell death, whereas sulforaphane-only and Se-only treatments showed very little if any protective effect. These results demonstrate that synergy can result from a combination of induction at the levels of transcription and translation.

Keywords: ARE, antioxidant response element; AREs, AU-rich elements; BSO, buthionine sulfoximine; CHX, cycloheximide; DMSO, dimethyl sulfoxide; DTNB, 5,5′-dithiobis (2-nitrobenzoic acid); GPx, glutathione peroxidase; H7, 1-(5-isoquinolinesulfonyl)-2-methyl-piperazine; HUVECs, human umbilical-vein endothelial cells; LDH, lactate dehydrogenase; PHGPx, phospholipid hydroperoxide glutathione peroxidase; PKC, protein kinase C; Se, selenium; SeCys, selenocysteine; SFN, sulforaphane; Trx, thioredoxin; TrxR, thioredoxin reductase

Journal Article.  6096 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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