Dietary chemopreventive compounds and ARE/EpRE signaling

Chemoprevention comprises multiple intervention methods using either pharmacological or dietary agents to impede, arrest, or reverse carcinogenesis at various stages. Development of dietary compounds as potential cancer chemopreventive agents is highly desirable, due to their safety, low toxicity, and general acceptance as dietary supplements. In this review, potential application of the dietary detoxifying enzyme inducers for chemoprevention and their relevant signaling events are discussed. Overall, the detoxifying enzyme system plays an important role in determining the final fate of carcinogens/procarcinogens and their subsequent impact on carcinogenesis. Among those positive regulators, phenolic and sulfur-containing compounds are two major classes of dietary detoxifying enzyme inducers. Regulation of many detoxifying enzymes by dietary chemopreventive compounds is mediated by the antioxidant response element (ARE)/electrophile response element (EpRE), which is located in the promoter region of related genes. Transcription factor nuclear factor E2-related factor 2 (Nrf2) binds to the ARE sequence to initiate gene expression. In response to treatments of various detoxifying enzyme inducers, several signal transduction pathways, including the oxidative stress, mitogen-active protein kinase, protein kinase C, and phosphatidylinositol 3-kinase pathways, are activated. The consequences of the activation of these signaling cascades, whether directly or indirectly, lead to the dissociation of Nrf2 from its cytosolic sequester Kelch-like ECH associating protein 1, nuclear translocation, and accumulation of Nrf2 protein in the nucleus, and ultimately increase the expression level of detoxifying enzymes through transcriptional activation of ARE/EpRE in those responsible genes.