The overall goal of this research is to elucidate the role of manganese superoxide dismutase (MnSOD) in the control of cancer development. It has been shown that most tumor cells have reduced MnSOD activity when compared to their normal counterparts. Recent studies have suggested the possibility that MnSOD may function as a new type of cancer suppressor gene. We have demonstrated that the expression of MnSOD suppresses neoplastic transformation and promotes differentiation. It has also been demonstrated in a variety of cancer cell lines that expression of MnSOD reduces tumorigenicity and metastatic capability. However, the specific stage and mechanisms by which MnSOD acts to suppress cancer development are unknown. We hypothesize that MnSOD suppresses tumor development at the promotion stage by modulating the endogenous cellular redox status which regulates the expression and/or activity of oncogenic proteins. To test this hypothesis, an established multistage skin carcinogenesis model will be used. The extent to which MnSOD suppresses cancer development will be determined in control and transgenic mice which express human MnSOD in their skin. The connection between the expression of human MnSOD transgene and 1) the production of mutated genes, 2) the formation of oxidative stress, 3) the expression and activity of proto-oncogenic proteins and their target genes, and 4) the development of inflammation, hyperplasia and skin tumors will be established. We have generated several lines of transgenic mice expressing human MnSOD genes in their skin. The strain of mice in which the transgenic mice were derived has been shown to develop tumors after an application of DMBA and daily applications of TPA. This transgenic mouse model should offer a powerful model for further investigating the tumor suppressor role of MnSOD. The results obtained from this study should provide direct data concerning the role of MnSOD in the process of cancer development and should enhance our understanding of the mechanism by which MnSOD directs the suppression of tumor genesis. This information may lead to the development of novel strategies to modulate the cellular redox status for the control of cancer development and the treatment of fully developed malignancies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA073599-02
Application #
2895851
Study Section
Chemical Pathology Study Section (CPA)
Program Officer
Okano, Paul
Project Start
1998-09-01
Project End
2001-08-31
Budget Start
1999-09-01
Budget End
2000-08-31
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Kentucky
Department
Pharmacology
Type
Schools of Medicine
DUNS #
832127323
City
Lexington
State
KY
Country
United States
Zip Code
40506
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Dhar, Sanjit Kumar; Zhang, Jiayu; Gal, Jozsef et al. (2014) FUsed in sarcoma is a novel regulator of manganese superoxide dismutase gene transcription. Antioxid Redox Signal 20:1550-66
Chaiswing, Luksana; Zhong, Weixiong; Oberley, Terry D (2014) Increasing discordant antioxidant protein levels and enzymatic activities contribute to increasing redox imbalance observed during human prostate cancer progression. Free Radic Biol Med 67:342-52
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Holley, Aaron K; Dhar, Sanjit Kumar; St Clair, Daret K (2013) Curbing cancer's sweet tooth: is there a role for MnSOD in regulation of the Warburg effect? Mitochondrion 13:170-88
Dong, Chenfang; Yuan, Tingting; Wu, Yadi et al. (2013) Loss of FBP1 by Snail-mediated repression provides metabolic advantages in basal-like breast cancer. Cancer Cell 23:316-31
Jorgenson, Tonia C; Zhong, Weixiong; Oberley, Terry D (2013) Redox imbalance and biochemical changes in cancer. Cancer Res 73:6118-23

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