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

TY - JOUR

T1 - Identification of retinoic acid as an inhibitor of transcription factor Nrf2 through activation of retinoic acid receptor alpha

AU - Wang, Xiu Jun

AU - Hayes, John D.

AU - Henderson, Colin J.

AU - Wolf, C. Roland

PY - 2007/12/4

Y1 - 2007/12/4

N2 - 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.

AB - 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.

KW - aldo-keto reductase

KW - chemoprevention

KW - Nrf2

KW - retinoids

KW - ANTIOXIDANT RESPONSE ELEMENT

KW - GLUTATHIONE-S-TRANSFERASE

KW - GENE-EXPRESSION

KW - DRUG-RESISTANCE

KW - AFLATOXIN B-1

KW - VITAMIN-A

KW - OXIDOREDUCTASE-1 GENE

KW - NEGATIVE REGULATION

KW - DEFICIENT MICE

KW - CELL-LINE

U2 - 10.1073/pnas.0709483104

DO - 10.1073/pnas.0709483104

M3 - Article

C2 - 18048326

SN - 0027-8424

VL - 104

SP - 19589

EP - 19594

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 49

ER -