Epigallocatechin gallate-induced modulation of FoxO signaling in mammalian cells and C. elegans: FoxO stimulation is masked via PI3K/Akt activation by hydrogen peroxide formed in cell culture

The green tea flavonoid epigallocatechin gallate (EGCG) is demonstrated in this study to modulate FoxO transcription factors in human skin fibroblasts in culture. EGCG at 1 μM stimulated FoxO transcription factor nuclear accumulation and DNA binding activity. This effect was masked at higher EGCG concentrations (100 μM) by EGCG-derived hydrogen peroxide generated in cell culture media that stimulates phosphoinositide-3′-kinase (PI3K)/Akt signaling to attenuate FoxO activity, involving FoxO phosphorylation, nuclear exclusion and attenuation of DNA binding activity. Like low concentrations of EGCG, harmine, an inhibitor of the FoxO kinase DYRK1a, stimulated FoxO nuclear accumulation and DNA binding activity. Exposure of Caenorhabditis elegans worms to EGCG caused nuclear accumulation of the FoxO ortholog, DAF-16, and enhanced expression of the DAF-16 target gene, sod-3. In line with the role of FoxO/DAF-16 in the control of life span, C. elegans mean and maximum life span were enhanced by 20% and 13%, respectively, by EGCG.