Mutant p53 blocks SESN1/AMPK/PGC-1α/UCP2 axis increasing mitochondrial O2ˉ· production in cancer cells. Issue 8 (16th October 2018)

• Record Type: Journal Article
• Authors: Cordani, Marco; Butera, Giovanna; Dando, Ilaria; Torrens-Mas, Margalida; Butturini, Elena; Pacchiana, Raffaella; Oppici, Elisa; Cavallini, Chiara; Gasperini, Sara; Tamassia, Nicola; Nadal-Serrano, Mercedes; Coan, Michela; Rossi, Davide; Gaidano, Gianluca; Caraglia, Michele; Mariotto, Sofia; Spizzo, Riccardo; Roca, Pilar; Oliver, Jordi; Scupoli, Maria; Donadelli, Massimo
• Is Part Of: British journal of cancer. Volume 119:Issue 8(2018)
• Page Start: 994
• Page End: 1008
• Publication Date: 2018-10-16
• Subjects: Cancer -- Periodicals; Cancer -- Research -- Periodicals; Tumors -- Periodicals; 616.994
• DOI: 10.1038/s41416-018-0288-2
• Languages: English
• ISSNs: 0007-0920

Abstract

Abstract Background TheTP53 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 differentTP53 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-1α/UCP2 axis and mitochondrial O2 ˉ· production. We also show a correlation between the decrease of reduced thiols with a poorer clinical outcome of CLL patients bearing mutantTP53 gene. The restoration of the mitochondrial uncoupling protein 2 (UCP2) expression, as well as the addition of the radical scavengerN -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-1α/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 mutantTP53 gene.