Activation of the Nrf2–ARE signaling pathway: a promising strategy in cancer prevention

A major protective mechanism against oxidizing substances capable of damaging DNA integrity and initiating carcinogenesis is the induction of phase II detoxification and antioxidant enzymes by chemopreventive agents. A key finding in the field of chemoprevention has been the discovery that the induction of these enzymes is mediated by the cytoplasmic oxidative stress system (Nrf2–Keap1). Under basal (reducing) conditions, Keap1 anchors the Nrf2 transcription factor within the cytoplasm, targeting it for ubiquitination and proteasome degradation, thus repressing its ability to induce phase II genes. When cells are exposed to chemopreventive agents and oxidative stress, however, a signal involving phosphorylation and/or redox modification is transmitted to the Nrf2–Keap1 complex, leading to its dissociation and the nuclear translocation of Nrf2, which, after heterodimerically partnering with other transcription factors, binds to the AREs/EpREs present within phase II gene promoters, increasing their transcription. These data should assist in developing new phase II detoxification enzyme inducers as cancer chemopreventive agents within the clinical environment. BioEssays 28: 169–181, 2006. © 2006 Wiley Periodicals, Inc.