Mutant p53 tunes the NRF2-dependent antioxidant response to support survival of cancer cells

Abstract

NRF2 (NFE2L2) is one of the main regulators of the antioxidant response of the cell. Here we show that in cancer cells NRF2 targets are selectively upregulated or repressed through a mutant p53-dependent mechanism. Mechanistically, mutant p53 interacts with NRF2, increases its nuclear presence and resides with NRF2 on selected ARE containing gene promoters activating the transcription of a specific set of genes while leading to the transcriptional repression of others. We show that thioredoxin (TXN) is a mutant p53-activated NRF2 target with pro-survival and pro-migratory functions in breast cancer cells under oxidative stress, while heme oxygenase 1 (HMOX1) is a mutant p53-repressed target displaying opposite effects. A gene signature of NRF2 targets activated by mutant p53 shows a significant association with bad overall prognosis and with mutant p53 status in breast cancer patients. Concomitant inhibition of thioredoxin system with Auranofin and of mutant p53 with APR-246 synergizes in killing cancer cells expressing p53 gain-of-function mutants.

A Splice Variant of NCOR2, BQ323636.1, Confers Chemoresistance in Breast Cancer by Altering the Activity of NRF2

“…Consistently, constitutive NRF2 activation can protect cancer cells from chemotherapy [21]. Aberrant NRF2 activation has been reported [42] to be mediated by a number of mechanisms, including somatic mutation of NRF2 and KEAP1 [43], DNA methylation of KEAP1 gene promoter [44], p62 accumulation which compete with NRF2 for KEAP1 [45] and transcriptional activation of NRF2 gene by other oncogenic factors (such as K-Ras, B-Raf, Myc, and mutant p53) [46][47][48][49]. However, the…”

Mutant p53-Associated Molecular Mechanisms of ROS Regulation in Cancer Cells

“…In this sense, mutant p53 may favor the nuclear translocation of Nrf2, thus redirecting it to the antioxidant response elements (ARE) in the promoter of Nrf2-target genes. This determines upregulation of thioredoxins (TXNs) and repression of detoxifying enzymes, such as NAD(P)H quinone dehydrogenase 1 (NQO1) and heme oxygenase 1 (HMOX1), resulting in intracellular ROS accumulation [133,134]. Interestingly, Liu et al demonstrated that mutant p53 proteins mediated the repression of the Nrf2 target gene SLC7A11, a component of the cystine/glutamate antiporter [135].…”

“…These studies support the existence of different mechanisms induced by mutant p53 proteins to modulate the expression of secreted inflammatory cytokines in order to sustain an inflammatory tumor microenvironment, thus potentially contributing to promote oxidative stress and increased cancer aggressiveness. [110,117,118,120,121] R175H, R248W, R273H NF-kB Lung, pancreatic, breast and colon cancer [158][159][160][161][162] R175H, R281G, R273H Cytokines Lung, breast, pancreatic and colon cancer [157,164,165] R175H, R273H PGC1-α Lung, colon and pancreatic cancer [8,137] R175H, R280K, R273H NRF2 Colon carcinoma, oesophageal adenocarcinoma, lung and breast cancer [133][134][135] R175H, R273H AMPK Pancreatic and breast cancer [8,89,110] R175H, R248H, R273H SESNs Breast and pancreatic cancer [8,89] R175H, R273H UCP2 Lung, pancreatic and breast cancer [8] R175H, R273H GSH Oesophageal adenocarcinoma, pancreatic and breast cancer [128,135] R175H, R273H Autophagy Lung carcinoma, pancreatic and breast cancer [89]…”

NSAID celecoxib: a potent mitochondrial pro-oxidant cytotoxic agent sensitizing metastatic cancers and cancer stem cells to chemotherapy

“…Recently, mutant p53 (mut-p53) was shown to interact with NRF2, increasing p53/NRF2 complexes on select antioxidant response element (ARE) containing gene promoters to activate transcription of a specific set of genes, whilst repressing most others [26][27][28] . In particular, the Trx gene (TXN) is unusual along with the thioredoxin reductase (TXNRD1) as mut-p53 activated NRF2 target genes enhancing the Trx system with pro-survival and pro-migratory functions in breast cancer cells under oxidative stress, while heme oxygenase 1 (HMOX1) is a mut-p53 repressed target displaying opposite effects [26] .…”

“…Recently, mutant p53 (mut-p53) was shown to interact with NRF2, increasing p53/NRF2 complexes on select antioxidant response element (ARE) containing gene promoters to activate transcription of a specific set of genes, whilst repressing most others [26][27][28] . In particular, the Trx gene (TXN) is unusual along with the thioredoxin reductase (TXNRD1) as mut-p53 activated NRF2 target genes enhancing the Trx system with pro-survival and pro-migratory functions in breast cancer cells under oxidative stress, while heme oxygenase 1 (HMOX1) is a mut-p53 repressed target displaying opposite effects [26] . Mut-p53 appears to sequester NRF2 preventing its activity on most of the NRF2 regulated genes impairing its canonical antioxidant activities, directly promoting greater ROS accumulation in cancer cells by inhibiting expression of the glutamate/cystine antiporter solute carrier family 7 member 11 (SLC7A11, also called xCT), a component of the cystine/glutamate antiporter as part of the Xc-system, diminishing cytosolic production of GSH [27,28] .…”