Oxidative stress responses and NRF2 in human leukaemia.
Oxidative stress as a result of elevated levels of reactive oxygen species (ROS) has been observed in almost all cancers, including leukaemia, where they contribute to disease development and progression. However, cancer cells also express increased levels of antioxidant proteins which detoxify ROS. This includes glutathione, the major antioxidant in human cells, which has recently been identified to have dysregulated metabolism in human leukaemia. This suggests that critical balance of intracellular ROS levels is required for cancer cell function, growth, and survival. Nuclear factor (erythroid-derived 2)-like 2 (NRF2) transcription factor plays a dual role in cancer. Primarily, NRF2 is a transcription factor functioning to protect nonmalignant cells from malignant transformation and oxidative stress through transcriptional activation of detoxifying and antioxidant enzymes. However, once malignant transformation has occurred within a cell, NRF2 functions to protect the tumour from oxidative stress and chemotherapy-induced cytotoxicity. Moreover, inhibition of the NRF2 oxidative stress pathway in leukaemia cells renders them more sensitive to cytotoxic chemotherapy. Our improved understanding of NRF2 biology in human leukaemia may permit mechanisms by which we could potentially improve future cancer therapies. This review highlights the mechanisms by which leukaemic cells exploit the NRF2/ROS response to promote their growth and survival.
Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich NR4 7UQ, UK.
Amina
A
Abdul-Aziz
Department of Molecular & Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE, UK.
David J
DJ
MacEwan
Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich NR4 7UQ, UK ; Department of Haematology, Norfolk and Norwich University Hospitals National Health Service Trust, Norwich NR4 7UY, UK.
Kristian M
KM
Bowles
Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich NR4 7UQ, UK.
Stuart A
SA
Rushworth
D000975:Antioxidants / Q000378:metabolism; D002470:Cell Survival; D004249:DNA Damage; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007938:Leukemia / Q000378:metabolism / Q000473:pathology*; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism
D000975:Antioxidants; D051267:NF-E2-Related Factor 2; D017382:Reactive Oxygen Species; D005978:Glutathione