QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: mol.105.018374v1 69/3/1033    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Andreadi, C. K. Articles by Manson, M. M. Search for Related Content PubMed PubMed Citation Articles by Andreadi, C. K. Articles by Manson, M. M.

Involvement of Nrf2, p38, B-Raf, and Nuclear Factor-B, but Not Phosphatidylinositol 3-Kinase, in Induction of Hemeoxygenase-1 by Dietary Polyphenols

Cancer Biomarkers and Prevention Group, Departments of Cancer Studies and Biochemistry, University of Leicester, Leicester, United Kingdom

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 µM) induced HO-1 in breast cells from 5 to 24 h. Curcumin (5-40 µM) or hemin (5-100 µM) 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 µM, 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-B (NF-B)-DNA binding inhibitor helenalin (20 µM) 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 µM) induced HO-1 only in wt MEFs. Results suggest that signaling through p38 mitogen-activated protein kinase, NF-B, 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 µM) of helenalin did not protect MDA-MB468 breast cells or B-lymphoblasts from apoptosis.

Address correspondence to: Prof. M. M. Manson, Cancer Biomarkers and Prevention Group, Departments of Cancer Studies and Biochemistry, Biocenter, University of Leicester, Leicester LE1 7RH, UK. E-mail: mmm2{at}le.ac.uk

This article has been cited by other articles:

				C. J. Baglole, P. J. Sime, and R. P. Phipps Cigarette smoke-induced expression of heme oxygenase-1 in human lung fibroblasts is regulated by intracellular glutathione Am J Physiol Lung Cell Mol Physiol, October 1, 2008; 295(4): L624 - L636. [Abstract] [Full Text] [PDF]

				S. Naidu, N. Wijayanti, S. Santoso, T. Kietzmann, and S. Immenschuh An Atypical NF-{kappa}B-Regulated Pathway Mediates Phorbol Ester-Dependent Heme Oxygenase-1 Gene Activation in Monocytes J. Immunol., September 15, 2008; 181(6): 4113 - 4123. [Abstract] [Full Text] [PDF]

				R. Garg, S. Gupta, and G. B. Maru Dietary curcumin modulates transcriptional regulators of phase I and phase II enzymes in benzo[a]pyrene-treated mice: mechanism of its anti-initiating action Carcinogenesis, May 1, 2008; 29(5): 1022 - 1032. [Abstract] [Full Text] [PDF]

				B. E. Bachmeier, I. V. Mohrenz, V. Mirisola, E. Schleicher, F. Romeo, C. Hohneke, M. Jochum, A. G. Nerlich, and U. Pfeffer Curcumin downregulates the inflammatory cytokines CXCL1 and -2 in breast cancer cells via NF{kappa}B Carcinogenesis, April 1, 2008; 29(4): 779 - 789. [Abstract] [Full Text] [PDF]

				H. Zhang and H. J. Forman Acrolein Induces Heme Oxygenase-1 through PKC-{delta} and PI3K in Human Bronchial Epithelial Cells Am. J. Respir. Cell Mol. Biol., April 1, 2008; 38(4): 483 - 490. [Abstract] [Full Text] [PDF]

				C.-H. Hsieh, C.-S. Rau, M.-W. Hsieh, Y.-C. Chen, S.-F. Jeng, T.-H. Lu, and S.-S. Chen Simvastatin-Induced Heme Oxygenase-1 Increases Apoptosis of Neuro 2A Cells in Response to Glucose Deprivation Toxicol. Sci., January 1, 2008; 101(1): 112 - 121. [Abstract] [Full Text] [PDF]

				B. S. Cornblatt, L. Ye, A. T. Dinkova-Kostova, M. Erb, J. W. Fahey, N. K. Singh, M.-S. A. Chen, T. Stierer, E. Garrett-Mayer, P. Argani, et al. Preclinical and clinical evaluation of sulforaphane for chemoprevention in the breast Carcinogenesis, July 1, 2007; 28(7): 1485 - 1490. [Abstract] [Full Text] [PDF]

				J. Alam and J. L. Cook How Many Transcription Factors Does It Take to Turn On the Heme Oxygenase-1 Gene? Am. J. Respir. Cell Mol. Biol., February 1, 2007; 36(2): 166 - 174. [Abstract] [Full Text] [PDF]