Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 44, Issue 8, Pages 1677-1686Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2008.01.022
Keywords
MnSOD; ROS; apoptosis; Bcl-2; Bax; oncogenesis; chroinosomal instability; free radicals
Funding
- NCI NIH HHS [F31 CA103362-03S1, R01 CA100045, F31 CA103362, R01 CA104695, P30 CA086862-069012, R01-CA100045, 5F31CA103362, R01 CA104695-04, P30 CA086862, P30-CA086862, R01 CA100045-04] Funding Source: Medline
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Increased reactive oxygen species (ROS) Such as superoxide have been implicated as causal elements of oncogenesis. A variety of cancers have displayed changes in steady-state levels of key antioxidant enzymes, with the mitochondrial form of superoxide dismutase (MnSOD) being commonly implicated. Increasing MnSOD expression suppresses the malignant phenotype in various cancer cell lines and suppresses tumor formation in xenograft and transgenic Mouse models. We examined the impact of MnSOD expression in the development of T cell lymphoma in mice expressing proapoptotic Bax. Lck-Bax38/1 transgenic mice were crossed to mice overexpressing MnSOD (Lek-MnSOD) as well as MnSOD+/- mice. The effects of MnSOD on apoptosis, cell cycle, chromosomal instability (CIN), and lymphoma, development were determined. The apoptotic and cell cycle phenotypes observed in thymocytes from control and Bax transgeme mice were unaffected by variations in MnSOD levels. Remarkably, increased gene dosage of MnSOD significantly decreased aneuploidy in premalignant thymocytes as well as the onset of tumor formation in Lek-Bax38/1 mice. The observed effects of MnSOD support a role for ROS in CIN and tumor fort-nation in this mouse model of T cell lymphoma. (c) 2008 Elsevier Inc. All rights reserved.
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