Abstract
Nuclear factor E2-related factor 2 (NRF2), a transcription factor, is a master regulator of an array of genes related to oxidative and electrophilic stress that promote and maintain redox homeostasis. NRF2 function is well studied in in vitro, animal and general physiology models. However, emerging data has uncovered novel functionality of this transcription factor in human diseases such as cancer, autism, anxiety disorders and diabetes. A key finding in these emerging roles has been its constitutive upregulation in multiple cancers promoting pro-survival phenotypes. The survivability pathways in these studies were mostly explained by classical NRF2 activation involving KEAP-1 relief and transcriptional induction of reactive oxygen species (ROS) neutralizing and cytoprotective drug-metabolizing enzymes (phase I, II, III and 0). Further, NRF2 status and activation is associated with lowered cancer therapeutic efficacy and the eventual emergence of therapeutic resistance. Interestingly, we and others have provided further evidence of direct NRF2 regulation of anticancer drug targets like receptor tyrosine kinases and DNA damage and repair proteins and kinases with implications for therapy outcome. This novel finding demonstrates a renewed role of NRF2 as a key modulatory factor informing anticancer therapeutic outcomes, which extends beyond its described classical role as a ROS regulator. This review will provide a knowledge base for these emerging roles of NRF2 in anticancer therapies involving feedback and feed forward models and will consolidate and present such findings in a systematic manner. This places NRF2 as a key determinant of action, effectiveness and resistance to anticancer therapy.
Highlights
Cancer drug resistanceA major road block in cancer patient care is the development of resistance where cancer cells become tolerant to pharmaceutical treatments[1]
This study demonstrated that Nuclear factor E2-related factor 2 (NRF2) activation can lead to a metastatic programme by inhibiting the heme and FBXO22-mediated degradation of BTB and CNC homology 1 (BACH1)
Nuclear NRF2 expression due to activation of NRF2-ARE signalling may promote tumor progression and drug resistance, and NRF2 inhibition could be a strategic path in cancer treatment[54,58,196]
Summary
Cancer drug resistanceA major road block in cancer patient care is the development of resistance where cancer cells become tolerant to pharmaceutical treatments[1]. Recent studies have shown that constitutive high level expression of NRF2 leads to tumor formation and drug resistance in cancer cells. Overexpression of Inhibitor of Apoptosis Stimulating Protein of p53 (iASPP), known as Rel A-associated inhibitor, in tumor cells has been demonstrated to promote cancer growth and drug resistance through high NRF2 levels.
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