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Identification of retinoic acid as an inhibitor of transcription factor Nrf2 through activation of retinoic acid receptor alpha.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2007 Dec 04; Vol. 104 (49), pp. 19589-94. Date of Electronic Publication: 2007 Nov 28. - Publication Year :
- 2007
-
Abstract
- Isothiocyanates and phenolic antioxidants can prevent cancer through activation of Nrf2 (NF-E2 p45-related factor 2), a transcription factor that controls expression of cytoprotective genes through the antioxidant response element (ARE) enhancer. Using a human mammary MCF7-derived AREc32 reporter cell line, we now report that all-trans retinoic acid (ATRA), and other retinoic acid receptor alpha (RARalpha) agonists, markedly reduces the ability of Nrf2 to mediate induction of ARE-driven genes by cancer chemopreventive agents including the metabolite of butylated hydroxyanisole, tert-butylhydroquinone (tBHQ). The basal and tBHQ-inducible expression of aldo-keto reductase (AKR) AKR1C1 and AKR1C2 genes, which are regulated by Nrf2, was also repressed by ATRA in AREc32 cells. Antagonists of RARalpha augmented induction of ARE-driven gene expression by tBHQ, as did knockdown of RARalpha by using RNAi. The expression of the ARE-gene battery was increased in the small intestine of mice fed on a vitamin A-deficient diet, and this increase was repressed by administration of ATRA. By contrast, in the small intestine of Nrf2 null mice, the expression of ARE-driven genes was not affected by vitamin A status. In MCF7 cells, ATRA did not block the nuclear accumulation of Nrf2 but reduced the binding of Nrf2 to the ARE enhancer as a consequence of forming a complex with RARalpha. These data suggest that cross-talk between Nrf2 and RARalpha could markedly influence the sensitivity of cells to electrophiles and oxidative stressors and, as a consequence, to carcinogenesis.
- Subjects :
- 20-Hydroxysteroid Dehydrogenases genetics
20-Hydroxysteroid Dehydrogenases metabolism
Animals
Antineoplastic Agents therapeutic use
Antioxidants pharmacology
Cell Line, Tumor
Cell Nucleus chemistry
Cell Nucleus metabolism
Chemoprevention
Enhancer Elements, Genetic
Gene Expression drug effects
Humans
Hydroquinones pharmacology
Hydroxysteroid Dehydrogenases genetics
Hydroxysteroid Dehydrogenases metabolism
Luciferases analysis
Luciferases genetics
Mice
Mice, Mutant Strains
NF-E2 Transcription Factor, p45 Subunit genetics
NF-E2 Transcription Factor, p45 Subunit metabolism
Response Elements
Retinoic Acid Receptor alpha
Tretinoin therapeutic use
Antineoplastic Agents pharmacology
NF-E2 Transcription Factor, p45 Subunit antagonists & inhibitors
Neoplasms prevention & control
Receptors, Retinoic Acid agonists
Tretinoin pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 104
- Issue :
- 49
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 18048326
- Full Text :
- https://doi.org/10.1073/pnas.0709483104