Absence of manganese superoxide dismutase delays p53-induced tumor formation.
BACKGROUND
Manganese superoxide dismutase (MnSOD) is a mitochondrial antioxidant enzyme that is down-regulated in a majority of cancers. Due to this observation, as well as MnSOD's potent antioxidant enzymatic activity, MnSOD has been suggested as a tumor suppressor for over 30 years. However, testing this postulate has proven difficult due to the early post-natal lethality of the MnSOD constitutive knock-out mouse. We have previously used a conditional tissue-specific MnSOD knock-out mouse to study the effects of MnSOD loss on the development of various cell types, but long-term cancer development studies have not been performed. We hypothesized the complete loss of MnSOD would significantly increase the rate of tumor formation in a tissue-specific manner.


RESULTS
Utilizing a hematopoietic stem cell specific Cre-recombinase mouse model, we created pan-hematopoietic cell MnSOD knock-out mice. Additionally, we combined this MnSOD knock-out with two well established models of lymphoma development: B-lymphocyte specific Myc over-expression and conditional pan-hematopoietic cell p53 knock-out. Mice were allowed to age unchallenged until illness or death had occurred. Contrary to our initial hypothesis, the loss of MnSOD alone was insufficient in causing an increase in tumor formation, but did cause significant life-shortening skin pathology in a strain-dependent manner. Moreover, the loss of MnSOD in conjunction with either Myc overexpression or p53 knock-out did not accelerate tumor formation, and in fact delayed lymphomagenesis in the p53 knock-out model.


CONCLUSIONS
Our findings strongly suggest that MnSOD does not act as a classical tumor suppressor in hematological tissues. Additionally, the complete loss of MnSOD may actually protect from tumor development by the creation of an unfavorable redox environment for tumor progression. In summary, these results in combination with our previous work suggest that MnSOD needs to be tightly regulated for proper cellular homeostasis, and altering the activity in either direction may lead to cellular dysfunction, oncogenesis, or death.
Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA ; Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Adam J
AJ
Case
Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA.
Frederick E
FE
Domann
D000818:Animals; D015972:Gene Expression Regulation, Neoplastic; D055786:Gene Knockout Techniques; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D008223:Lymphoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D009374:Neoplasms, Experimental; D009928:Organ Specificity; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D000099156:Superoxide Dismutase 2
D016271:Proto-Oncogene Proteins c-myc; D013482:Superoxide Dismutase; D016159:Tumor Suppressor Protein p53; D000099156:Superoxide Dismutase 2; C489428:Myc protein, mouse
Anti-oxidant; Cancer; FoxO, Forkhead family of transcription factors; MnSOD, manganese superoxide dismutase; Oxidative stress; Pro-oxidant; Redox