The purpose of this proposal is to continue our study of the role of the enzyme superoxide dismutase (SOB) in cancer. This protective enzyme has been found, in general, to be low in tumor cells when compared to an appropriate control. We propose in this application to study at the molecular level why this enzyme is diminished in tumor cells and to determine what, if any, significance this loss has to the cancer cell phenotype. Work will be continued on two in vitro cell systems. In these systems four enzymes will be studied: copper and zinc-containing SOD (CuZnSOD), manganese-containing SOD (MnSOD), catalase (CAT), and glutathione peroxidase (GPX). The following will be measured: enzyme activity, immunoreactive protein using Western blotting, mRNA for the antioxidant enzymes using Northern blotting and in vitro translation, and gene copy number and gross gene rearrangements using Southern blotting. To determine the significance of the loss of SOD in tumor cells, transfection experiments with MnSOD cDNA will be performed. An expression vector for sense MnSOD cDNA will be transfected into tumor cells and clones that stably express high MnSOD isolated. These clones will then be tested for malignant properties. Immortal, non-malignant cells will also be transfected with sense MnSOD cDNA and clones with high MnSOD isolated. Clones expressing high MnSOD will then be tested for susceptibility to transformation and the results compared to controls. Similar experiments will be performed with non-differentiating, non-malignant cells to determine if expression of MnSOD allows differentiation to proceed. Likewise, a vector that contains the antisense cDNA for MnSOD will be transfected into normal cells and the effect on the phenotype studied. Cells transfected with antisense MnSOD cDNA will also be studied for susceptibility to carcinogenesis and for differentiation potential. These experiments should define the role of MnSOD malignancy. If MnSOD is found to be responsible for part of the cancer cell phenotype, modulation of this enzyme might be useful in preventing or treating cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Chemical Pathology Study Section (CPA)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Iowa
Schools of Medicine
Iowa City
United States
Zip Code
Miller Jr, Francis J; Sharp, William J; Fang, Xiang et al. (2002) Oxidative stress in human abdominal aortic aneurysms: a potential mediator of aneurysmal remodeling. Arterioscler Thromb Vasc Biol 22:560-5
Zhong, W; Yan, T; Lim, R et al. (1999) Expression of superoxide dismutases, catalase, and glutathione peroxidase in glioma cells. Free Radic Biol Med 27:1334-45
Li, N; Oberley, T D; Oberley, L W et al. (1998) Inhibition of cell growth in NIH/3T3 fibroblasts by overexpression of manganese superoxide dismutase: mechanistic studies. J Cell Physiol 175:359-69
Polavarapu, R; Spitz, D R; Sim, J E et al. (1998) Increased lipid peroxidation and impaired antioxidant enzyme function is associated with pathological liver injury in experimental alcoholic liver disease in rats fed diets high in corn oil and fish oil. Hepatology 27:1317-23
Liu, R; Oberley, T D; Oberley, L W (1998) Effects of endothelial nitric oxide synthase gene expression on the tumor biology of human oral carcinoma SCC-25 cells. Cell Growth Differ 9:239-46
Li, N; Oberley, T D; Oberley, L W et al. (1998) Overexpression of manganese superoxide dismutase in DU145 human prostate carcinoma cells has multiple effects on cell phenotype. Prostate 35:221-33
Li, J J; Oberley, L W; Fan, M et al. (1998) Inhibition of AP-1 and NF-kappaB by manganese-containing superoxide dismutase in human breast cancer cells. FASEB J 12:1713-23
Li, J J; Oberley, L W (1997) Overexpression of manganese-containing superoxide dismutase confers resistance to the cytotoxicity of tumor necrosis factor alpha and/or hyperthermia. Cancer Res 57:1991-8
Baker, A M; Oberley, L W; Cohen, M B (1997) Expression of antioxidant enzymes in human prostatic adenocarcinoma. Prostate 32:229-33
Zhong, W; Oberley, L W; Oberley, T D et al. (1997) Suppression of the malignant phenotype of human glioma cells by overexpression of manganese superoxide dismutase. Oncogene 14:481-90

Showing the most recent 10 out of 57 publications