Identification of retinoic acid as an inhibitor of transcription factor Nrf2 through activation of retinoic acid receptor alpha.
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.
Cancer Research U.K. Molecular Pharmacology Unit, Biomedical Research Centre, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, United Kingdom.
Xiu Jun
XJ
Wang
John D
JD
Hayes
Colin J
CJ
Henderson
C Roland
CR
Wolf
D015089:20-Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000975:Antioxidants / Q000494:pharmacology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000737:chemistry / Q000378:metabolism; D018890:Chemoprevention; D004742:Enhancer Elements, Genetic; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D006873:Hydroquinones / Q000494:pharmacology; D006913:Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000378:metabolism; D008156:Luciferases / Q000032:analysis / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains; D050984:NF-E2 Transcription Factor, p45 Subunit / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000517:prevention & control*; D018168:Receptors, Retinoic Acid / Q000819:agonists*; D020218:Response Elements; D000072482:Retinoic Acid Receptor alpha; D014212:Tretinoin / Q000494:pharmacology* / Q000627:therapeutic use; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)
D015089:20-Hydroxysteroid Dehydrogenases; D000970:Antineoplastic Agents; D000975:Antioxidants; D006873:Hydroquinones; D006913:Hydroxysteroid Dehydrogenases; D008156:Luciferases; D050984:NF-E2 Transcription Factor, p45 Subunit; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014212:Tretinoin; C000607071:RARA protein, human; C000607072:Rara protein, mouse; C018855:2-tert-butylhydroquinone; C115140:3 alpha-beta, 20 beta-hydroxysteroid dehydrogenase; C435496:AKR1C2 protein, human; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)