Cordani, MarcoButera, GiovannaDando, IlariaTorrens-Mas, MargalidaButturini, ElenaPacchiana, RaffaellaOppici, ElisaCavallini, ChiaraGasperini, SaraTamassia, NicolaNadal-Serrano, MercedesCoan, MichelaRossi, DavideGaidano, GianlucaCaraglia, MicheleMariotto, SofiaSpizzo, RiccardoRoca, PilarOliver, JordiScupoli, Maria TeresaDonadelli, Massimo2024-09-062024-09-062018-10-16Cordani M, Butera G, Dando I, Torrens-Mas M, Butturini E, Pacchiana R, et al. Mutant p53 blocks SESN1/AMPK/PGC-1 alpha/UCP2 axis increasing mitochondrial O-2-center dot production in cancer cells. Br J Cancer. 2018 Oct 16;119(8):994-1008. Epub 2018 Oct 15.0007-0920http://hdl.handle.net/20.500.13003/9071https://hdl.handle.net/20.500.12105/22597BACKGROUND: 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.enghttp://creativecommons.org/licenses/by/4.0/research articleAttribution 4.0 International303185201198994-100810.1038/s41416-018-0288-21532-1827British Journal of Canceropen accessLínea Celular TumoralProteína p53 Supresora de TumorFemeninoProteínas de Choque TérmicoCélulas MCF-7MasculinoAcetilcisteínaHumanosPersona de Mediana EdadNeoplasiasCoactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gammaAncianoProteínas Quinasas Activadas por AMPEspecies Reactivas de OxígenoProteína Desacopladora 2Anciano de 80 o más AñosOxígenoAdultoDepuradores de Radicales LibresMitocondrias2-s2.0-85055045363448407100013L624434618