Mutant p53 induces SIRT3/MnSOD axis to moderate ROS production in melanoma cells
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...
| Authors: | , , , , , , , , , |
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| Format: | article |
| Publication Date: | 2020 |
| Country: | España |
| Institution: | Conselleria de Salut i Consum del Govern de les Illes Balears |
| Repository: | Docusalut |
| Language: | English |
| OAI Identifier: | oai:docusalut.com:20.500.13003/20196 |
| Online Access: | https://hdl.handle.net/20.500.13003/20196 |
| Access Level: | Open access |
| Keyword: | Mutation Acetylation Reactive Oxygen Species Tumor Suppressor Protein p53 Humans Superoxide Dismutase Cell Line, Tumor Sirtuin 3 Melanoma Línea Celular Tumoral Proteína p53 Supresora de Tumor Humanos Especies Reactivas de Oxígeno Acetilación Sirtuina 3 Mutación Superóxido Dismutasa |
| Summary: | 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. |
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