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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Identification of retinoic acid as an inhibitor of transcription factor Nrf2 through activation of retinoic acid receptor alpha
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Identification of retinoic acid as an inhibitor of transcription factor Nrf2 through activation of retinoic acid receptor alpha

机译：通过激活视黄酸受体α，鉴定视黄酸作为转录因子Nrf2的抑制剂

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摘要

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 (RARa) 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 RARa augmented induction of ARE-driven gene expression by tBHQ, as did knockdown of RARa 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 RARa. These data suggest that cross-talk between Nrf2 and RARa could markedly influence the sensitivity of cells to electrophiles and oxidative stressors and, as a consequence, to carcinogenesis.
机译：异硫氰酸盐和酚类抗氧化剂可通过激活Nrf2（NF-E2 p45相关因子2）来预防癌症，Nrf2是通过抗氧化剂响应元件（ARE）增强子控制细胞保护性基因表达的转录因子。现在，我们使用人类乳腺MCF7衍生的AREc32报告细胞系报道，全反式维甲酸（ATRA）和其他维甲酸受体α（RARa）激动剂，明显降低了Nrf2介导诱导ARE驱动基因的能力通过癌症化学预防剂，包括丁基化羟基茴香醚的代谢产物，叔丁基对苯二酚（tBHQ）。在AREc32细胞中，ATRA还抑制了由Nrf2调控的醛基酮还原酶（AKR）AKR1C1和AKR1C2基因的基础表达和tBHQ诱导表达。 RARa拮抗剂与tRNA的结合增强了tBHQ对ARE驱动基因表达的诱导作用，而使用RNAi抑制RARa也是如此。在缺乏维生素A的饮食喂养的小鼠的小肠中，ARE基因电池的表达增加，而通过ATRA给药可抑制这种增加。相比之下，在Nrf2无效小鼠的小肠中，ARE驱动基因的表达不受维生素A状态的影响。在MCF7细胞中，ATRA不会阻断Nrf2的核积累，但会由于与RARa形成复合物而降低Nrf2与ARE增强子的结合。这些数据表明，Nrf2和RARa之间的串扰可能显着影响细胞对亲电试剂和氧化应激源的敏感性，并因此影响癌变。

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