Untitled Document

Research

Terry D. Oberley

M.D., Ph.D., Northwestern University
Professor, Department of Pathology and Laboratory Medicine
toberley@wisc.edu
http://www.terry-oberley.net/

Role of Antioxidant Enzymes and Reactive Oxygen Species in Cancer and Aging

My laboratory is studying the role that oxidative stress may play in both cancer and aging. It is well known that the risk of cancer increases with age, and many studies have suggested possible links between cancer and aging. My laboratory is studying the hypothesis that oxidative stress is at least partially responsible for the cancer and aging phenotypes.

Reactive oxygen species are forms of molecular oxygen with enhanced chemical reactivity. Excess levels of reactive oxygen species result in oxidative stress. One of the major protective mechanisms against injury caused by reactive oxygen species are the antioxidant enzymes. My laboratory is studying regulation of antioxidant enzymes in cancer, and we have found at least one abnormality in antioxidant enzymes in all cancers examined to date. We have hypothesized that antioxidant enzyme imbalance may affect cancer cell behavior. To test this hypothesis, we have placed the cDNA for one antioxidant enzyme into cancer cells and have shown that cancer cell growth is greatly suppressed. My laboratory is studying the mechanism by which growth arrest occurs. To date, we have shown that overexpression of antioxidant enzymes affects both cell signaling and the function of mitochondria to inhibit cell growth.

Aging is more likely a process that affects nondividing cells; this is in contrast to cancer in which dividing cells are the target of the malignant process. One current hypothesis of aging is that oxidative stress injures mitochondria in the nondividing cells, thus injuring the cells. To test this hypothesis, my laboratory is using antibodies specific for oxidative damage to determine the subcellular location of oxidative products in aging tissues.

If oxidative stress can be proved to be involved in cancer and/or aging, new possible therapies may result.

Representative Publications
Oberley, T.D., Swanlund, J.M., Zhang, H.J., & Kregel, K.C. (2008). Aging results in increased autophagy of mitochondria and protein nitration in rat hepatocytes following heat stress. J. Histochem. Cytochem., 56(6), 615-27.

Swanlund, J.M., Kregel, K.C, & Oberley, T.D. (2008). Autophagy following heat stress: the role of aging and protein nitration. Autophagy, 4 (7), 936-9.

Bourdeau-Heller, J., & Oberley, T.D. (2007). Prostate carcinoma cells selected by long-term exposure to reduced oxygen tension show remarkable biochemical plasticity via modulation of superoxide, HIF-1alpha levels, and energy metabolism. J. Cell. Physiol., 212(3), 744-52.

Aziz, M.H., Manoharan, H.T., Church, D.R., Dreckschmidt, N.E., Zhong, W., Oberley, T.D., Wilding, G., & Verma, A.K. (2007). Protein kinase Cepsilon interacts with signal transducers and activators of transcription 3 (Stat3), phosphorylates Stat3Ser727, and regulates its constitutive activation in prostate cancer. Cancer Res., 67(18), 8828-38.

Chaiswing, L., Cole, M.P., Ittarat, W., Szweda, L.I., St. Clair, D.K., & Oberley, T.D. (2005). Manganese superoxide dismutase and inducible nitric oxide synthase modify early oxidative events in acute adriamycin-induced mitochondrial toxicity. Mol. Cancer. Ther., 4(7),1056-64.

Kim, A., Murphy, M.P., & Oberley, T.D. (2005). Mitochondrial redox state regulates transcription of the nuclear-encoded mitochondrial protein manganese superoxide dismutase: a proposed adaptive response to mitochondrial redox imbalance. Free Radic. Biol. Med., 38(5), 644-54.

Kim, A., Oberley, L.W., & Oberley, T.D. (2005). Induction of apoptosis by adenovirus-mediated manganese superoxide dismutase overexpression in SV-40-transformed human fibroblasts. Free Radic. Biol. Med., 39(9), 1128-41.

Elchuri, S., Oberley, T.D., Qi, W., Eisenstein, R.S., Jackson, Roberts L., Van Remmen, H., Epstein, C.J., & Huang, T.T. (2005). CuZnSOD deficiency leads to persistent and widespread oxidative damage and hepatocarcinogenesis later in life. Oncogene, 24(3), 367-80.

Kim A., Zhong, W., & Oberley, T.D. (2004). Reversible modulation of cell cycle kinetics in NIH/3T3 mouse fibroblasts by inducible overexpression of mitochondrial manganese superoxide dismutase. Antioxid. Redox. Signal, 6(3), 489-500.

Oberley, T.D., Xue, Y., Zhao, Y., Kiningham, K., Szweda, L.I., & St. Clair, D.K. (2004). In situ reduction of oxidative damage, increased cell turnover, and delay of mitochondrial injury by overexpression of manganese superoxide dismutase in a multistage skin carcinogenesis model. Antioxid. Redox. Signal, 6(3), 537-48.

Oberley, T.D. (2004). Mitochondria, manganese superoxide dismutase, and cancer. Antioxid. Redox. Signal, 6(3), 483-7.

Chaiswing, L., Cole, M.P., St. Clair, D.K., Ittarat, W., Szweda, L.I., & Oberley, T.D. (2004). Oxidative damage precedes nitrative damage in adriamycin-induced cardiac mitochondrial injury. Toxicol. Pathol., 32(5), 536-47.

Oberley, T.D. (2002). Ultrastructural localization and relative quantification of 4-hydroxynonenal-modified proteins in tissues and cell compartments. Methods in Enzymology, 352, 373-377.

Oberley, T.D. (2001). Oxidative damage and cancer. Amer. J. Path., 160, 403-408.

Hall, D.M., Oberley, T.D., Moseley, P.M., Oberley, L.W., Weindruch, R., & Kregel, K.C. (2000). Caloric restriction improves thermotolerance and reduces hyperthermia-induced cellular damage in old rats. FASEB J., 14, 78-86.

Zainal, T.A., Oberley, T.D., Allison, D.B., Szweda, L.I., & Weindruch, R. (2000). Caloric restriction of rhesus monkeys lowers oxidative damage in skeletal muscle. FASEB J., 14, 1825-1836.

Oberley, T.D., Zhong, W., Szweda, L.I., & Oberley, L.W. (2000). Localization of antioxidant enzymes and oxidative damage products in normal and malignant prostate epithelium. Prostate, 44, 144-155.

Oberley, T.D., & Zainal, T.A. (2000). Morphologic assessment of oxidative damage: A review. Age, 23, 17-24.

Pugh, T.D., Oberley, T.D., & Weindruch, R. (1999). Dietary intervention at middle age: caloric restriction but not dehydroepiandrosterone sulfate increases lifespan and lifetime cancer incidence in mice. Cancer Res., 59, 1642-1648.

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