2026-05-22T00:44:13Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/225972024-11-28T19:17:02Zcom_20.500.12105_15322com_20.500.12105_2051col_20.500.12105_16963col_20.500.12105_16967
Repisalud
author
Cordani, Marco
author
Butera, Giovanna
author
Dando, Ilaria
author
Torrens-Mas, Margalida
author
Butturini, Elena
author
Pacchiana, Raffaella
author
Oppici, Elisa
author
Cavallini, Chiara
author
Gasperini, Sara
author
Tamassia, Nicola
author
Nadal-Serrano, Mercedes
author
Coan, Michela
author
Rossi, Davide
author
Gaidano, Gianluca
author
Caraglia, Michele
author
Mariotto, Sofia
author
Spizzo, Riccardo
author
Roca, Pilar
author
Oliver, Jordi
author
Scupoli, Maria Teresa
author
Donadelli, Massimo
2024-09-06T09:56:03Z
2024-09-06T09:56:03Z
2018-10-16
Cordani 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.
10.1038/s41416-018-0288-2
1532-1827
0007-0920
British Journal of Cancer
http://hdl.handle.net/20.500.13003/9071
30318520
L624434618
2-s2.0-85055045363
https://hdl.handle.net/20.500.12105/22597
448407100013
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.
eng
Mutant p53 blocks SESN1/AMPK/PGC-1 alpha/UCP2 axis increasing mitochondrial O-2-center dot production in cancer cells
research article