Torrens-Mas, MargalidaCordani, MarcoMullappilly, NidulaPacchiana, RaffaellaRiganti, ChiaraPalmieri, MartaPons, Daniel-GabrielRoca, PilarOliver, JordiDonadelli, Massimo2024-09-132024-09-132020-01-15Torrens-Mas M, Cordani M, Mullappilly N, Pacchiana R, Riganti C, Palmieri M, et al. Mutant p53 induces SIRT3/MnSOD axis to moderate ROS production in melanoma cells. Arch Biochem Biophys. 2020 Jan 15;679:108219.https://hdl.handle.net/20.500.13003/20196https://hdl.handle.net/20.500.12105/22882This is an postprint (Accepted Manuscript) of an article published by Elsevier in Archives of Biochemistry and Biophysics on 2019 December5, available online: https://doi.org/10.1016/j.abb.2019.108219The TP53 tumor suppressor gene is the most frequently altered gene in tumors and mutant p53 isoforms can acquire oncogenic properties referred to as gain-of-function (GOF). In this study, we used wild-type (A375) and mutant p53 (MeWo) melanoma cell lines to assess the regulation of the mitochondrial antioxidant manganese superoxide dismutase (MnSOD) by mutant p53. The effects of mutant p53 were evaluated by qPCR, immunoblotting, enzyme activity assay, cell proliferation assay, reactive oxygen species (ROS) assay after cellular transfection. We demonstrate that mutant p53 induces MnSOD expression, which is recovered by the ROS scavenger N-acetyl-l-cysteine. This suggests MnSOD induction as a defense mechanism of melanoma cells to counterbalance the pro-oxidant conditions induced by mutant p53. We also demonstrate that mutant p53 induces the expression of Sirtuin3 (SIRT3), a major mitochondrial NAD+-dependent deacetylase, stimulating MnSOD deacetylation and enzymatic activity. Indeed, the restoration of SIRT3 reverses MnSOD activity decrease by mutant p53 knock-down. Finally, MnSOD knock-down further enhances mutant p53-mediated ROS increase, counteracting mutp53-dependent cell hyperproliferation. This indicates that SIRT3 and MnSOD act to maintain ROS levels controlled to promote cell proliferation and survival, providing new therapeutic opportunities to be further considered for clinical studies in cancer patients bearing mutant TP53 gene.engAMhttp://creativecommons.org/licenses/by-nc-nd/4.0/MutationAcetylationReactive Oxygen SpeciesTumor Suppressor Protein p53HumansSuperoxide DismutaseCell Line, TumorSirtuin 3MelanomaAttribution-NonCommercial-NoDerivatives 4.0 Internacional3181266867910821910.1016/j.abb.2019.1082191096-0384Archives of biochemistry and biophysicsopen accessLínea Celular TumoralProteína p53 Supresora de TumorHumanosMelanomaEspecies Reactivas de OxígenoAcetilaciónSirtuina 3MutaciónSuperóxido Dismutasa2-s2.0-85076026927525443900014L2004161197