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The regulation and functions of transcription factor Nrf2 in cancer chemoprevention and chemoresistance

Lin-Ling Que, Hui-Xia Wang, Bao-Shan Cao, Xiao-Da Yang, Kui Wang, Si-Wang Yu*   

  1. 1. Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191 China
    2. Department of Oncology, Cancer Center, Peking University Third Hospital, Beijing 100191 China
  • Received:2010-12-12 Revised:2010-01-05 Online:2011-01-15 Published:2011-01-15
  • Contact: Si-Wang Yu*


Chemotherapy and chemoprevention have been two of the most important means to control cancer incidence and mortality, and the cellular defensive machinery against oxidative/electrophilic stresses plays significant roles in both means. This defensive system is composed of cytoprotective enzymes that metabolize and eliminate oxidative/electrophilic species. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) controls the basal and inducible expression of many cytoprotective genes, and plays a pivotal role in coordinating cellular defensive responses. Under basal conditions, the activity of Nrf2 is inhibited by binding to Kelch-like ECH-associated protein 1 (Keap1), which is capable of sensing oxidative/electrophilic signals. Upon oxidative/electrophilic stresses, the binding of Nrf2 to Keap1 is disrupted, leading to activation of Nrf2 and induction of cytoprotective enzymes. Thus, Nrf2 has emerged as an important target of chemopreventive drugs. However, activation of Nrf2 could lead to very different outcomes depending on the cellular context. The indiscriminative protective effects of Nrf2 lead to its undesired functions in carcinogenesis and chemoresistance of cancer cells. Activation of Nrf2 provides neoplastic cells with growth advantages and protects cancer cells from chemotherapeutic drugs, resulting in poor clinical outcomes. In this means, inhibitors of Nrf2 signaling can enhance the efficacy of chemotherapeutic drugs and deserve further development. A better understanding of the regulation and functions of Nrf2 would be helpful for researches in both chemoprevention and chemotherapy of cancer.

Key words: Nrf2, Oxidative/electrophilic stress, Carcinogenesis, Chemoprevention, Chemoresistance

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