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化学进展 2013, Vol. 25 Issue (09): 1544-1552 DOI: 10.7536/PC130718 前一篇   后一篇

• 癌症化学预防专辑 •

Nrf2通路在肿瘤化学预防中的研究进展

王秀君*1, 李欣2, 唐修文*2   

  1. 1. 浙江大学医学院药理学系 杭州310058;
    2. 浙江大学医学院生物化学和遗传学系 杭州310058
  • 收稿日期:2013-03-01 修回日期:2013-06-01 出版日期:2013-09-25 发布日期:2013-07-31
  • 通讯作者: 王秀君, 唐修文 E-mail:xjwang@zju.edu.cn; xiuwentang@zju.edu.cn
  • 基金资助:

    国家自然科学基金项目(No. 81172230, 31170743, 30970581, 3097355, 31370772),浙江省科技厅项目(No. 2010C33156,2011C23078)和浙江省自然科学基金项目(No. LZ12H16001)资助

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The Role of Nrf2 in Carcinogenesis

Wang Xiu Jun*1, Li Xin2, Tang Xiuwen*2   

  1. 1. Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou 310058, China;
    2. Department of Biochemistry and Genetics, School of Medicine, Zhejiang University, Hangzhou 310058, China
  • Received:2013-03-01 Revised:2013-06-01 Online:2013-09-25 Published:2013-07-31

转录因子E2 相关因子2(Nrf2)通过与抗氧化反应元件(ARE)结合正向调控Ⅱ相解毒酶基因、抗氧化酶基因及药物转运泵基因等靶基因的表达。在正常条件下Nrf2 与 Kelch 样环氧氯丙烷相关蛋白(KEAP1) 在细胞质中结合导致其被蛋白酶体降解;当细胞受亲电试剂或活性氧进攻时,Nrf2 蛋白水平增加并移位于细胞核,激活多种细胞保护基因的转录。近年来Nrf2 通路在癌细胞中的作用越来越受关注,本文概括了Nrf2/ARE 信号通路的调控机制,讨论了Nrf2 在肿瘤化学预防和癌症发生双方面的作用,归纳了影响Nrf2 通路小分子化合物的筛选方法和Nrf2 抑制剂的研究进展。

关键词： Nrf2, 抗氧化反应元件, 化学预防

The nuclear factor erythroid-2 related factor 2 (Nrf2) is a pivotal activator of genes encoding cytoprotective and detoxifying enzymes that protect against oxidative and eletrophilic stress. Under normal condition, Nrf2 is localized in the cytoplasm binding to Kelch-like ECH-associated protein 1 (KEAP1), which facilitates the degradation of Nrf2 via the ubiquitin proteasome pathway. Under stress conditions, oxidants or electrophiles abrogate the interaction between KEAP1 with Nrf2, resulting in increased nuclear accumulation of Nrf2 and the transcriptional induction of target genes. Activation of Nrf2 pathway is crucial for cancer chemoprevention. However, over-expression of Nrf2 has been found in many types of cancer, facilitating tumor growth and resistance to anticancer therapy. This article summarises recent progress in understanding the regulation of Nrf2 activity, and the new development in finding small molecules modulating Nrf2/ARE signalling pathway.

Contents
1 Introduction
2 Dual roles of Nrf2 in carcinogenesis
2.1 Activation of Nrf2 is important for cancer chemoprevention
2.2 The dependence of tumour cells on Nrf2
3 The complexity of Nrf2 signaling
3.1 KEAP1-independent Nrf2 degradation
3.2 p21 activates Nrf2 through direct interacting with NRF2
3.3 p62 activates Nrf2 through interacting with KEAP1
3.4 Oncogenes activate Nrf2
3.5 Nuclear receptors inhibit Nrf2 activity
4 Small molecules modulate Nrf2/ARE signalling pathway
4.1 The methods used for identifying novel Nrf2 activators
4.2 The Nrf2 inhibitors
5 Concluding remarks

Key words: Nrf2, ARE, chemoprevention

中图分类号: 

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