Identification of retinoic acid as an inhibitor of transcription factor Nrf2 through activation of retinoic acid receptor alpha

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    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.
    Original languageEnglish
    Pages (from-to)19589-19594
    Number of pages6
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume104
    Issue number49
    DOIs
    Publication statusPublished - 4 Dec 2007

    Keywords

    • aldo-keto reductase
    • chemoprevention
    • Nrf2
    • retinoids
    • ANTIOXIDANT RESPONSE ELEMENT
    • GLUTATHIONE-S-TRANSFERASE
    • GENE-EXPRESSION
    • DRUG-RESISTANCE
    • AFLATOXIN B-1
    • VITAMIN-A
    • OXIDOREDUCTASE-1 GENE
    • NEGATIVE REGULATION
    • DEFICIENT MICE
    • CELL-LINE

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