© 1999 by Oxford University Press
Journal of the National Cancer Institute, Vol. 91, No. 14, 1227-1232,
July 21, 1999
© 1999 Oxford University Press
REPORTS |
Effect of Antioxidants on Androgen-Induced AP-1 and NF-
B DNA-Binding Activity in Prostate Carcinoma Cells
Affiliations of authors: M. O. Ripple, S. R. Schwarze, Institute on Aging, University of Wisconsin, Madison, and Geriatric Research, Education and Clinical Center, William S. Middleton Memorial Veterans Hospital, Madison; W. F. Henry, G. Wilding, Department of Medicine, University of Wisconsin Comprehensive Cancer Center, Madison; R. Weindruch, Institute on Aging, University of Wisconsin, Geriatric Research, Education and Clinical Center, William S. Middleton Memorial Veterans Hospital, and Department of Medicine, University of Wisconsin Comprehensive Cancer Center, Madison.
Correspondence to: George Wilding, M.D., Department of Medicine, University of Wisconsin, K6/550 CSC, 600 Highland Ave., Madison, WI 53792.
BACKGROUND: Previous studies have suggested that male hormones (androgens) and certain
forms of oxygen (reactive oxygen species) are linked to the development of prostate cancer. We
hypothesized that androgens contribute to prostate carcinogenesis by increasing oxidative stress.
We further hypothesized that antioxidants reduce prostate cancer risk by modulating androgen
effects on cellular processes. METHODS: To test these hypotheses, we looked for 1) a change in
the level of reactive oxygen species in the presence of androgens, 2) androgen-induced binding
activity of transcriptional activators AP-1 and NF-
B, whose activities are known to be
altered during cell proliferation, and 3) the effect of antioxidants on androgen-induced
transcription factor binding. RESULTS: Physiologic concentrations (1 nM) of
5
-dihydrotestosterone or 1-10 nM R1881, a synthetic androgen, produced
sustained elevation of AP-1 and NF-B DNA-binding activity in LNCaP cells, an
androgen-responsive human prostate carcinoma cell line. Androgen-independent DU145 cells
(another human prostate carcinoma cell line) were unaffected by R1881 treatment. AP-1-binding
activity increased 5 hours after 1 nM R1881 treatment; NF-B DNA-binding
activity increased after 36 hours. Both activities remained elevated for at least 120 hours. Nuclear
AP-1 and NF-B protein levels were not elevated. Antioxidant vitamins C plus E blocked
both androgen-induced DNA-binding activity and production of reactive oxygen species.
CONCLUSION: Physiologic concentrations of androgens induce production of reactive oxygen
species and cause prolonged AP-1 and NF-B DNA-binding activities, which are diminished
by vitamins C and E.
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