Involvement of Nrf2, P38, B-raf, and Nuclear Factor-kappab, but Not Phosphatidylinositol 3-kinase, in Induction of Hemeoxygenase-1 by Dietary Polyphenols.
From: Cancer Biomarkers and Prevention Group, Department of Cancer Studies, Biocenter, University of Leicester, Leicester LE1 7RH, UK.
Molecular pharmacology
- Publish Date: Mar 2006
- ISSN: 0026-895X
- Volume: 69
- Issue: 3
- Pages: 1033-40
- Medium: Print
- Language: English
- Citation (JAMA): Andreadi Catherine K, Howells Lynne M, Atherfold Paul A, et al. Involvement of Nrf2, P38, B-raf, and Nuclear Factor-kappab, but Not Phosphatidylinositol 3-kinase, in Induction of Hemeoxygenase-1 by Dietary Polyphenols.. Mol. Pharmacol. Mar 2006;69:1033-40
Abstract
The highly inducible enzyme, hemeoxygenase-1 (HO-1), metabolizes heme, thereby protecting a variety of cells against oxidative stress and apoptosis. Up-regulation by cancer chemopreventive agents has been reported, but its regulation and function in transformed cells are unclear. We compared induction by two dietary polyphenols, curcumin and epigallocatechin-3-gallate (EGCG), with that by the endogenous substrate hemin in epithelial and endothelial cells and examined the relevance to apoptosis. Curcumin or hemin (20 microM) induced HO-1 in breast cells from 5 to 24 h. Curcumin (5-40 microM) or hemin (5-100 microM) induced HO-1 and nuclear levels of nuclear factor (erythroid-derived 2)-related factor (Nrf2) in a dose-dependent manner. EGCG had no effect in breast cells, but at 30 microM, it induced nuclear translocation of Nrf2 and HO-1 expression in B-lymphoblasts. In all cases, induction was inhibited by pretreatment with the phosphatidylinositol 3-kinase (PI3K) inhibitor 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002) or the p38 inhibitor 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole (SB203580). The nuclear factor-kappaB (NF-kappaB)-DNA binding inhibitor helenalin (20 microM) also prevented induction. However, wortmannin had no effect, suggesting that PI3K was not involved. Curcumin and hemin also induced nuclear Nrf2 and HO-1 effectively in wild-type mouse embryo fibroblasts (wt MEFs) and in B-Raf(-/-) MEFs but not in Nrf2(-/-) MEFs. However, EGCG (5-20 microM) induced HO-1 only in wt MEFs. Results suggest that signaling through p38 mitogen-activated protein kinase, NF-kappaB, and Nrf2 as well as other unidentified molecules is involved in HO-1 induction by hemin and both polyphenols, but cell-specific factors also play a role, particularly with respect to EGCG. Induction of HO-1 by curcumin, EGCG, or low concentrations (5-10 microM) of helenalin did not protect MDA-MB468 breast cells or B-lymphoblasts from apoptosis.
Mesh Headings (Keywords): 1-Phosphatidylinositol 3-Kinase, Animals, Apoptosis, B-Lymphocytes, Breast, Catechin, Cell Nucleus, Cells, Cultured, Curcumin, Diet, Fibroblasts, Flavonoids, Heme Oxygenase-1, Humans, Mice, Mice, Knockout, NF-E2-Related Factor 2, NF-kappa B, Phenols, Sesquiterpenes, p38 Mitogen-Activated Protein Kinases
Check for Full Text / PubMed Unique Identifier (PMID): 16354769
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