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oai:repisalud.isciii.es:20.500.12105/228822024-11-28T22:49:02Zcom_20.500.12105_15322com_20.500.12105_2051col_20.500.12105_16967

00925njm 22002777a 4500 dc Torrens-Mas, Margalida author Cordani, Marco author Mullappilly, Nidula author Pacchiana, Raffaella author Riganti, Chiara author Palmieri, Marta author Pons, Daniel-Gabriel author Roca, Pilar author Oliver, Jordi author Donadelli, Massimo author 2020-01-15 The 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. Torrens-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. 10.1016/j.abb.2019.108219 1096-0384 Archives of biochemistry and biophysics https://hdl.handle.net/20.500.13003/20196 31812668 L2004161197 2-s2.0-85076026927 https://hdl.handle.net/20.500.12105/22882 525443900014 Mutant p53 induces SIRT3/MnSOD axis to moderate ROS production in melanoma cells