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[Cancer Research 61, 6082-6088, August 15, 2001]
© 2001 American Association for Cancer Research

Carcinogenesis

Overexpression of Manganese Superoxide Dismutase Suppresses Tumor Formation by Modulation of Activator Protein-1 Signaling in a Multistage Skin Carcinogenesis Model1

Yunfeng Zhao, Yi Xue, Terry D. Oberley, Kelley K. Kiningham, Shu-Mei Lin, Hsiu-Chuan Yen2, Hideyuki Majima3, Judy Hines and Daret St. Clair4

Graduate Center for Toxicology, University of Kentucky, Lexington, Kentucky 40536 [Y. Z., K. K. K., S-M. L., H-C. Y., H. M., J. H., D. S. C.], and Department of Pathology [Y. X., T. D. O.] and Veterans Affairs Hospital [T. D. O.], University of Wisconsin, Madison, Wisconsin 53705

Manganese superoxide dismutase (MnSOD) is a nuclear encoded primary antioxidant enzyme localized in mitochondria. Because expression of MnSOD plays a major role in maintaining cellular redox status and reactive oxygen species are known to play a role in signal transduction and carcinogenesis, we investigated the role of MnSOD in the development of cancer using a two-stage [7,12-dimethylbenz(a)-anthracene plus 12-O-tetradecanoylphorbol-13-acetate (TPA)] skin carcinogenesis model. Female transgenic mice expressing the human MnSOD gene in the skin and their nontransgenic counterparts were used in this study. Pathological examination demonstrated significant reduction of papilloma formation in transgenic mice. Quantitative analysis of 4-hydroxy-2-nonenal-modified proteins showed greater accumulation of oxidative damage products in nontransgenic compared with transgenic mice, and this oxidative damage was demonstrated to be present in both mitochondria and nucleus. TPA increased activator protein-1 (AP-1) binding activity within 6 h in nontransgenic mice, but increased AP-1 binding activity was delayed in the transgenic mice. Electrophoretic mobility shift assay, transcription of the target genes, and Western analysis studies indicated that the increased AP-1 binding activity was attributable to induction of the Jun but not the Fos protein families. Overexpression of MnSOD selectively inhibited the TPA-induced activation of protein kinase C{epsilon} and prevented subsequent activation of c-Jun NH2-terminal kinase in response to TPA. Overall, these results indicate that MnSOD regulates both cellular redox status and selectively modulates PKC{epsilon} signaling, thereby delaying AP-1 activation and inhibiting tumor promotion, resulting in reduction of tumors in MnSOD transgenic mice.




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Copyright © 2001 by the American Association for Cancer Research.