Dual roles of Nrf2 in cancer

Abstract

In response to oxidative stress, the transcription factor NF-E2-related factor 2 (Nrf2) controls the fate of cells through transcriptional upregulation of antioxidant response element (ARE)-bearing genes, including those encoding endogenous antioxidants, phase II detoxifying enzymes, and transporters. Expression of the Nrf2-dependent proteins is critical for ameliorating or eliminating toxicants/carcinogens to maintain cellular redox homeostasis. As a result, activation of the Nrf2 pathway, by naturally-occurring compounds or synthetic chemicals at sub-toxic doses, confers protection against subsequent toxic/carcinogenic exposure. Thus, the use of dietary compounds or synthetic chemicals to boost the Nrf2-dependent adaptive response to counteract environmental insults has emerged to be a promising strategy for cancer prevention. Interestingly, recent emerging data has revealed the "dark" side of Nrf2. Nrf2 and its downstream genes are overexpressed in many cancer cell lines and human cancer tissues, giving cancer cells an advantage for survival and growth. Furthermore, Nrf2 is upregulated in resistant cancer cells and is thought to be responsible for acquired chemoresistance. Therefore, it may be necessary to inhibit the Nrf2 pathway during chemotherapy. This review is primarily focused on the role of Nrf2 in cancer, with emphasis on the recent findings indicating the cancer promoting function of Nrf2 and its role in acquired chemoresistance.

Schematic model of Nrf2 regulation by Keap1

Keap1 is a key regulator of the Nrf2 signaling pathway and serves as a molecular switch to turn on and off the Nrf2-mediated antioxidant response. (i) The switch is in off position: under basal conditions, Keap1, functioning as an E3 ubiquitin ligase, constantly targets Nrf2 for ubiquitination and degradation. As a consequence, there are minimal levels of Nrf2. (ii) The switch is turned on: oxidative stress or chemopreventive compounds inhibit activity of the Keap1-Cul3-Rbx1 E3 ubiquitin ligase, resulting in increased levels of Nrf2 and activation of its downstream target genes. (iii) The switch is turned off again: Upon recovery of cellular redox homeostasis, Keap1 travels into the nucleus to remove Nrf2 from the ARE. The Nrf2-Keap1 complex is then transported out of the nucleus by the NES in Keap1. In the cytosol, the Nrf2-Keap1 complex associates with the Cul3-Rbx1 core ubiquitin machinery, leading to degradation of Nrf2. For clarity, the constitutive cytoplasmic-nuclear shuttling of Nrf2, Keap1, and the complex is omitted.