Abstract
The gene expression program induced by NRF2 transcription factor plays a critical role in cell defense responses against a broad variety of cellular stresses, most importantly oxidative stress. NRF2 stability is fine-tuned regulated by KEAP1, which drives its degradation in the absence of oxidative stress. In the context of cancer, NRF2 cytoprotective functions were initially linked to anti-oncogenic properties. However, in the last few decades, growing evidence indicates that NRF2 acts as a tumor driver, inducing metastasis and resistance to chemotherapy. Constitutive activation of NRF2 has been found to be frequent in several tumors, including some lung cancer sub-types and it has been associated to the maintenance of a malignant cell phenotype. This apparently contradictory effect of the NRF2/KEAP1 signaling pathway in cancer (cell protection against cancer versus pro-tumoral properties) has generated a great controversy about its functions in this disease. In this review, we will describe the molecular mechanism regulating this signaling pathway in physiological conditions and summarize the most important findings related to the role of NRF2/KEAP1 in lung cancer. The focus will be placed on NRF2 activation mechanisms, the implication of those in lung cancer progression and current therapeutic strategies directed at blocking NRF2 action.
Highlights
Lung cancer, one of the most commonly diagnosed malignancies, has some of the lowest 5-year survival rates and is responsible for around 20% of all cancer-related deaths worldwide [1,2]
Increased PD-L1 expression is associated with NFE2L2 mutations in LUSC and KEAP1 mutations in LUAD. These findings suggest that NFE2L2/KEAP1 mutations/activation could be of benefit for LUSC and LUAD treatment by immunotherapy [223,224]
Further research is needed to verify the correlation between immunotherapy and NRF2 pathway activation in clinical trials, this study suggests that high NRF2 activity tumors, LUAD, could benefit from this treatment [106]
Summary
One of the most commonly diagnosed malignancies, has some of the lowest 5-year survival rates and is responsible for around 20% of all cancer-related deaths worldwide [1,2]. The Neh domain is a serine rich region that is involved in the regulation of NRF2 stability [13] It contains two amino acid motifs (DSGIS and DSAPGS), which are binding sites for the β-transducin repeat-containing protein (β-TrCP) that promote NRF2 poly-ubiquitination [36,37]. The DGR/Kelch domain binds to the ETGE (or STGE) and DLG amino acid motifs of different partners including the NRF2 Neh domain [41,47,48] p62, B-cell lymphoma extra-large (Bcl-xL), dipeptidyl Peptidase 3 (DPP3), splicing factor, arginine/serine-rich 10 (SFRS10), D-site of albumin promoter binding protein (DBP), etc. Several oxidative and electrophilic cellular stressors can directly modify critical KEAP1 Cys residues (Cys257, Cys273, Cys288, Cys297 and Cys151) by oxido-reduction and/or alkylation reactions [54,55] Their redox modifications cause a conformational change that disrupts KelchDLG binding, avoiding the NRF2 degradation by the proteasome. Members of Src subfamily A, like Fyn, are able to phosphorylate NRF2 in the nucleus for its nuclear export and degradation [61] (Figure 3B)
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