Projects per year
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.
Original language | English |
---|---|
Article number | 3609 |
Number of pages | 48 |
Journal | Cancers |
Volume | 12 |
Issue number | 12 |
DOIs | |
Publication status | Published - 2 Dec 2020 |
Keywords
- NRF2
- KEAP1
- Cullin 3
- ATF4
- oxidative stress
- reactive oxygen species
- antioxidant
- adaptation
- glutathione
- thioredoxin
- NADPH generation
- pentose phosphate pathway
- proteasome
- autophagy
- drug metabolism
- chemoprevention
- chemotherapy
- bioactivation
- quinone-containing drugs
- drug resistance
- oncogene
- tumour suppressor
- initiation
- progression
- metastasis
- recurrent disease
- lung
- oesophagus
- liver
- head and neck
- stomach
- bladder
- colon
- rectum
- Quinone-containing drugs
- Bioactivation
- Liver
- Lung
- Metastasis
- Drug resistance
- Recurrent disease
- Drug metabolism
- Head and neck
- Initiation
- Proteasome
- Oesophagus
- Chemotherapy
- Rectum
- Progression
- Oxidative stress
- Reactive oxygen species
- Bladder
- Thioredoxin
- Autophagy
- Colon
- Adaptation
- Glutathione
- Stomach
- Chemoprevention
- Oncogene
- Antioxidant
- Pentose phosphate pathway
- Tumour suppressor
ASJC Scopus subject areas
- Oncology
- Cancer Research
Fingerprint
Dive into the research topics of 'NRF2 and the Ambiguous Consequences of Its Activation during Initiation and the Subsequent Stages of Tumourigenesis'. Together they form a unique fingerprint.-
Defining the Oxidative Stress-Related Mechanisms by which Activation of the Transcription Factor Nrf2 Arrests and Resolves Liver Fibrosis
Arthur, S. (Investigator), Dillon, J. (Investigator), Dinkova-Kostova, A. (Investigator), Hayes, J. (Investigator) & Henderson, C. (Investigator)
1/04/20 → 30/06/25
Project: Research
-
Contribution by NRF2 Upregulation to Lung Carcinogenesis and the Possible Therapeutic Value of NRF2 Inhibition by GSK-3 (Joint with Universities of St Andrews, Edinburgh and Pennsylvania)
Dinkova-Kostova, A. (Investigator), Hayes, J. (Investigator), Henderson, C. (Investigator), Keyse, S. (Investigator), Lamond, A. (Investigator) & Sutherland, C. (Investigator)
1/05/16 → 31/10/19
Project: Research
Profiles
-
Hayes, John
- Cancer Research - Professor (Teaching and Research) of Molecular Carcinogenesis
Person: Academic