Mutant p53 blocks SESN1/AMPK/PGC-1 alpha/UCP2 axis increasing mitochondrial O-2-center dot production in cancer cells
BACKGROUND: The TP53 tumor suppressor gene is the most frequently altered gene in tumors and mutant p53 gain-of-function isoforms actively promote cancer malignancy. METHODS: A panel of wild-type and mutant p53 cancer cell lines of different tissues, including pancreas, breast, skin, and lung were u...
| Autores: | , , , , , , , , , , , , , , , , , , , , |
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| Tipo de recurso: | artículo |
| Fecha de publicación: | 2018 |
| País: | España |
| Institución: | Conselleria de Salut i Consum del Govern de les Illes Balears |
| Repositorio: | Docusalut |
| Idioma: | inglés |
| OAI Identifier: | oai:docusalut.com:20.500.13003/9071 |
| Acceso en línea: | https://hdl.handle.net/20.500.13003/9071 |
| Access Level: | acceso abierto |
| Palabra clave: | Oxygen Free Radical Scavengers Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha Tumor Suppressor Protein p53 Uncoupling Protein 2 Female AMP-Activated Protein Kinases Heat-Shock Proteins Male MCF-7 Cells Neoplasms Acetylcysteine Middle Aged Cell Line, Tumor Humans Reactive Oxygen Species Adult Mitochondria Aged Aged, 80 and over Mitocondrias Línea Celular Tumoral Proteína p53 Supresora de Tumor Femenino Proteínas de Choque Térmico Células MCF-7 Masculino Acetilcisteína Humanos Persona de Mediana Edad Neoplasias Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma Anciano Proteínas Quinasas Activadas por AMP Especies Reactivas de Oxígeno Proteína Desacopladora 2 Anciano de 80 o más Años Oxígeno Adulto Depuradores de Radicales Libres |
| Sumario: | BACKGROUND: The TP53 tumor suppressor gene is the most frequently altered gene in tumors and mutant p53 gain-of-function isoforms actively promote cancer malignancy. METHODS: A panel of wild-type and mutant p53 cancer cell lines of different tissues, including pancreas, breast, skin, and lung were used, as well as chronic lymphocytic leukemia (CLL) patients with different TP53 gene status. The effects of mutant p53 were evaluated by confocal microscopy, reactive oxygen species production assay, immunoblotting, and quantitative reverse transcription polymerase chain reaction after cellular transfection. RESULTS: We demonstrate that oncogenic mutant p53 isoforms are able to inhibit SESN1 expression and consequently the amount of SESN1/AMPK complex, resulting in the downregulation of the AMPK/PGC-1 alpha/UCP2 axis and mitochondrial O-2(-)center dot production. We also show a correlation between the decrease of reduced thiols with a poorer clinical outcome of CLL patients bearing mutant TP53 gene. The restoration of the mitochondrial uncoupling protein 2 (UCP2) expression, as well as the addition of the radical scavenger N-acetyl-L-cysteine, reversed the oncogenic effects of mutant p53 as cellular hyper-proliferation, antiapoptotic effect, and resistance to drugs. CONCLUSIONS: The inhibition of the SESN1/AMPK/PGC-1 alpha/UCP2 axis contributes to the pro-oxidant and oncogenic effects of mutant p53, suggesting pro-oxidant drugs as a therapeutic approach for cancer patients bearing mutant TP53 gene. |
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