Green tea polyphenol and curcumin inversely regulate human involucrin promoter activity via opposing effects on CCAAT/enhancer-binding protein function.
- 1Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106-4970, USA.
Abstract
Antioxidants are important candidate agents for the prevention of disease. However, the possibility that different antioxidants may produce opposing effects in tissues has not been adequately explored. We have reported previously that (-)-epigallocatechin-3-gallate (EGCG), a green tea polyphenol antioxidant, stimulates expression of the keratinocyte differentiation marker, involucrin (hINV), via a Ras, MEKK1, MEK3, p38delta signaling cascade (Balasubramanian, S., Efimova, T., and Eckert, R. L. (2002) J. Biol. Chem. 277, 1828-1836). We now show that EGCG activation of this pathway results in increased CCAAT/enhancer-binding protein (C/EBPalpha and C/EBPbeta) factor level and increased complex formation at the hINV promoter C/EBP DNA binding site. This binding is associated with increased promoter activity. Mutation of the hINV promoter C/EBP binding site eliminates the regulation as does expression of GADD153, a dominant-negative C/EBP factor. In contrast, a second antioxidant, curcumin, inhibits the EGCG-dependent promoter activation. This is associated with inhibition of the EGCG-dependent increase in C/EBP factor level and C/EBP factor binding to the hINV promoter. Curcumin also inhibits the EGCG-dependent increase in endogenous hINV levels. The curcumin-dependent suppression of C/EBP factor level is inhibited by treatment with the proteasome inhibitor MG132, suggesting that the proteasome function is required for curcumin action. We conclude that curcumin and EGCG produce opposing effects on involucrin gene expression via regulation of C/EBP factor function. The observation that two antioxidants can produce opposite effects is an important consideration in the context of therapeutic antioxidant use.
It's not clear how any of this relates to cancer. Studies done at University of Florida indicate synergy between EGCG, curcumin and sulforaphane as an anti-glioma therapy in mouse models.
ReplyDeletehttp://neuro-oncology.oxfordjournals.org/content/16/suppl_5/v82.2.short?rss=1
I don't like the model used in that paper and the conclusions drawn from their results.
ReplyDeleteThe examined responses at gene called involucrin (hINV). Expression of this gene changes when cells called keratinocytes (skin cells) differentiate (develop). Because curcumin and EGCG can have opposing effects on this one gene, they suggest these supplements cancel each other out. The problem is that both compounds regulate multiple genes and might regulate genes differently in various types of cells.
I agree with Stephen would suggest benefits from the combination. I like synergy with TMZ.