Manganese superoxide dismutase: Beyond life and death

Aaron K. Holley, Sanjit Kumar Dhar, Yong Xu, Daret K.St Clair

Research output: Contribution to journalArticlepeer-review

88 Scopus citations

Abstract

Manganese superoxide dismutase (MnSOD) is a nuclear-encoded antioxidant enzyme that localizes to the mitochondria. Expression of MnSOD is essential for the survival of aerobic life. Transgenic mice expressing a luciferase reporter gene under the control of the human MnSOD promoter demonstrate that the level of MnSOD is reduced prior to the formation of cancer. Overexpression of MnSOD in transgenic mice reduces the incidences and multiplicity of papillomas in a DMBA/TPA skin carcinogenesis model. However, MnSOD deficiency does not lead to enhanced tumorigenicity of skin tissue similarly treated because MnSOD can modulate both the p53-mediated apoptosis and AP-1-mediated cell proliferation pathways. Apoptosis is associated with an increase in mitochondrial levels of p53 suggesting a link between MnSOD deficiency and mitochondrial-mediated apoptosis. Activation of p53 is preventable by application of a SOD mimetic (MnTE-2- PyP 5+). Thus, p53 translocation to mitochondria and subsequent inactivation of MnSOD explain the observed mitochondrial dysfunction that leads to transcriptiondependent mechanisms of p53-induced apoptosis. Administration of MnTE-2-PyP 5+ following apoptosis but prior to proliferation leads to suppression of protein carbonyls and reduces the activity of AP-1 and the level of the proliferating cellular nuclear antigen, without reducing the activity of p53 or DNA fragmentation following TPA treatment. Remarkably, the incidence and multiplicity of skin tumors are drastically reduced in mice that receive MnTE-2-PyP 5+ prior to cell proliferation. The results demonstrate the role of MnSOD beyond its essential role for survival and suggest a novel strategy for an antioxidant approach to cancer intervention.

Original languageEnglish
Pages (from-to)139-158
Number of pages20
JournalAmino Acids
Volume42
Issue number1
DOIs
StatePublished - Jan 2012

Keywords

  • Cancer
  • Chemotherapy
  • MnSOD
  • p53

ASJC Scopus subject areas

  • Biochemistry
  • Organic Chemistry
  • Clinical Biochemistry

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