Mutant p53 tunes the NRF2-dependent antioxidant response to support survival of cancer cells
| Autor: | Dawid Walerych, Yari Ciani, Elena Campaner, Giannino Del Sal, Kamil Lisek |
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| Přispěvatelé: | Lisek, Kamil, Campaner, Elena, Ciani, Yari, Walerych, Dawid, Del Sal, Giannino |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
HMOX1 Auranofin Mutant environment and public health NRF2 03 medical and health sciences medicine cancer oxidative stress Cancer Mutant p53 Oxidative stress Oncology Chemistry mutant p53 Promoter respiratory system NFE2L2 Cell biology Heme oxygenase 030104 developmental biology Cancer cell Oxidative stre Thioredoxin medicine.drug Research Paper |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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