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Manganese Superoxide Dismutase Induces p53-Dependent Senescence in Colorectal Cancer Cells

Behrend, Lars and Mohr, Andrea and Dick, Tatjana and Zwacka, Ralf M (2005) 'Manganese Superoxide Dismutase Induces p53-Dependent Senescence in Colorectal Cancer Cells.' Molecular and Cellular Biology, 25 (17). pp. 7758-7769. ISSN 0270-7306

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<jats:title>ABSTRACT</jats:title> <jats:p> The mitochondrial enzyme manganese superoxide dismutase (MnSOD) is known to suppress cell growth in different tumor cell lines. However, the molecular mechanism of this growth-retarding effect is not fully understood. Here we show that overexpression of MnSOD slows down growth of HCT116 human colorectal cancer cells by induction of cellular senescence. MnSOD overexpression causes up-regulation of p53 and its transcriptional target, the cyclin-dependent kinase inhibitor p21. Adenovirus-mediated knockdown of p53 by RNA interference rescues MnSOD-overexpressing clones from growth retardation. Accordingly, the overexpression of MnSOD in HCTp53 <jats:sup>−/−</jats:sup> cells does not lead to senescence, whereas in HCTp21 <jats:sup>−/−</jats:sup> cells we found induction of senescence by forced expression of MnSOD. These results indicate a pivotal role of p53, but not p21, in the observed effects. Analysis of the mitochondrial membrane potential revealed reduced polarization in MnSOD-overexpressing cells. In addition, depolarization of the mitochondrial membrane by mitochondrial inhibitors such as rotenone or antimycin A led colorectal cancer cells into p53-dependent senescence. Our data indicate that uncoupling of the electrochemical gradient by increased MnSOD activity gives rise to p53 up-regulation and induction of senescence. This novel mitochondrially mediated mechanism of tumor suppression might enable strategies that allow reactivation of cellular aging in tumor cells. </jats:p>

Item Type: Article
Uncontrolled Keywords: Cell Line; Intracellular Membranes; Mitochondria; Humans; Colorectal Neoplasms; Matrix Metalloproteinases; Superoxide Dismutase; Cell Cycle Proteins; Cell Proliferation; Transcription, Genetic; Gene Expression Regulation, Neoplastic; Up-Regulation; Tumor Suppressor Protein p53; Cyclin-Dependent Kinase Inhibitor p21; Cellular Senescence
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Divisions: Faculty of Science and Health
Faculty of Science and Health > Life Sciences, School of
SWORD Depositor: Elements
Depositing User: Elements
Date Deposited: 29 Jun 2017 10:17
Last Modified: 15 Jan 2022 00:34

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