Emerging role of nuclear factor erythroid 2-related factor 2 in the mechanism of action and resistance to anticancer therapies

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.

A Nature-Inspired Nrf2 Activator Protects Retinal Explants from Oxidative Stress and Neurodegeneration

“…Our data show that NIH1-induced Nrf2 nuclear translocation is correlated with an increase of Nrf2 mRNA levels. This is consistent with data showing that, once in the nucleus, Nrf2 binds the antioxidant response element (ARE) sequences and induces its own expression via a positive feedback [ 55 , 56 ]. Moreover, the binding of Nrf2 to ARE also causes the transcription of phase II antioxidant enzymes, including HO-1 and NQO1 [ 57 ].…”

Nanoencapsulation of basil essential oil alleviates the oxidative stress, genotoxicity and DNA damage in rats exposed to biosynthesized iron nanoparticles

“…In addition, EBEO increases the levels of other natural antioxidants in the body, such as SOD and CAT which protect the liver from PAR-induced hepatotoxicity ( El-Banna et al., 2013 ). The mechanisms postulated to BEO as antioxidants including (1) scavenging of ROS; (2) chelation of iron which initiates radical reactions and inhibition of enzymes responsible for the generation of ROS ( Edenharder and Gruñhage, 2003 ); (3) antioxidants can interfere with xenobiotic-metabolizing enzymes, block activated mutagens/carcinogens, modulate DNA repair and even regulate gene expression ( Paramasivan et al., 2019 ). All these mechanisms may be important for their antimutagenic and anticarcinogenic properties ( De Flora and Ferguson, 2005 ).…”

Oxidative Stress Induces a VEGF Autocrine Loop in the Retina: Relevance for Diabetic Retinopathy

“…In this regard, it should be noted that the Nrf2 blocker that we used in these studies, ML385, does not interfere with Nrf2 nuclear translocation, but blocks Nrf2 transcriptional activity by interfering with binding of Nrf2 to the ARE in the promoter region of Nrf2 target genes [ 33 ]. On the other hand, it has been reported that Nrf2 binding to ARE not only promotes antioxidant gene expression, but also triggers a positive feedback loop leading to further Nrf2 expression [ 34 , 35 ]. Therefore, our immunofluorescence observations, summarized in Figure 5 , may reflect the fact that OS results both in increased Nrf2 nuclear translocation and in increased Nrf2 expression, while treatment with ML385 inhibits Nrf2-triggered Nrf2 expression, thereby reducing significantly the amount of Nrf2 that may translocate to the nucleus.…”