NRF2 and the Ambiguous Consequences of Its Activation during Initiation and the Subsequent Stages of Tumourigenesis

Abstract

NF-E2 p45-related factor 2 (NRF2, encoded in the human by NFE2L2) mediates short-term adaptation to thiol-reactive stressors. In normal cells, activation of NRF2 by a thiol-reactive stressor helps prevent, for a limited period of time, the initiation of cancer by chemical carcinogens through induction of genes encoding drug-metabolising enzymes. However, in many tumour types, NRF2 is permanently upregulated. In such cases, its overexpressed target genes support the promotion and progression of cancer by suppressing oxidative stress, because they constitutively increase the capacity to scavenge reactive oxygen species (ROS), and they support cell proliferation by increasing ribonucleotide synthesis, serine biosynthesis and autophagy. Herein, we describe cancer chemoprevention and the discovery of the essential role played by NRF2 in orchestrating protection against chemical carcinogenesis. We similarly describe the discoveries of somatic mutations in NFE2L2 and the gene encoding the principal NRF2 repressor, Kelch-like ECH-associated protein 1 (KEAP1) along with that encoding a component of the E3 ubiquitin-ligase complex Cullin 3 (CUL3), which result in permanent activation of NRF2, and the recognition that such mutations occur frequently in many types of cancer. Notably, mutations in NFE2L2, KEAP1 and CUL3 that cause persistent upregulation of NRF2 often co-exist with mutations that activate KRAS and the PI3K-PKB/Akt pathway, suggesting NRF2 supports growth of tumours in which KRAS or PKB/Akt are hyperactive. Besides somatic mutations, NRF2 activation in human tumours can occur by other means, such as alternative splicing that results in a NRF2 protein which lacks the KEAP1-binding domain or overexpression of other KEAP1-binding partners that compete with NRF2. Lastly, as NRF2 upregulation is associated with resistance to cancer chemotherapy and radiotherapy, we describe strategies that might be employed to suppress growth and overcome drug resistance in tumours with overactive NRF2.

The diverse functionality of NQO1 and its roles in redox control

“…One aspect of NQO1 induction that has been recently exploited is the activation of antitumor compounds by NQO1 in tumors that have aberrant and persistent Nrf2 upregulation as a result of activating mutations in the Keap1-Nrf2 pathway and other mechanisms [ 141 ]. Nrf2 is activated in many tumor types and such tumors often exhibit resistance to existing therapies resulting in poor patient outcomes [ 141 ]. This has led to the development of Keap1 knockout cell line screens for the identification of compounds that exhibit synthetic lethality with Nrf2 overexpression [ 142 , 143 ].…”

“…However, additional molecules such as the aurora kinase inhibitor AT9283 have also been identified in these screens for selective killing of tumor cells with elevated Nrf2 levels [ 147 ] which do not have obvious links to NQO1-mediated bioreductive activation, although NQO1 has been reported to bind directly to aurora A [ 148 ]. A more complete analysis of compounds activated in cells with activated Nrf2 is detailed in the original references [ 142 , 143 , 147 ] and in a comprehensive recent review by Hayes and colleagues [ 141 ].…”

Quantitative Proteomics Reveals the Antitumor Effects of Sodium New Houttuyfonate on Non-small Cell Lung Cancer

“…38,39 The Nrf2 signaling is crucial for the growth and survival of cancer cells. 40 In this study, SNH upregulated the expression of a set of Nrf2mediated oxidative stress response-related proteins, including heme oxygenase 1 (HMOX1) and sequestosome-1 (SQSTM1/ p62) (the downstream targets of Nrf2) (Fig. 4, Table S1).…”

Sulforaphane Impact on Reactive Oxygen Species (ROS) in Bladder Carcinoma

“…Still, the relevance of the Nrf2-pathway in bladder cancer is not fully understood. Overexpression of Nrf2 is suggested to support the promotion and progression of cancer by suppressing oxidative stress via scavenging ROS [ 68 ]. Studies on bladder cancer cells present evidence that p62 promotes tumor cell growth by activating Keap1-Nrf2 signaling [ 69 ].…”