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Clinical Cancer Research Vol. 7, 824-830, April 2001
© 2001 American Association for Cancer Research

Molecular Oncology, Markers, Clinical Correlates

Elevated and Altered Expression of the Multifunctional DNA Base Excision Repair and Redox Enzyme Ape1/ref-1 in Prostate Cancer1

Mark R. Kelley2, Liang Cheng, Richard Foster, Renee Tritt, Jiazhong Jiang, John Broshears and Michael Koch

Departments of Pediatrics (Section of Hematology/Oncology) and Biochemistry & Molecular Biology, Herman B Wells Center for Pediatric Research [M. R. K., R. T. ], and Departments of Pathology [L. C., J. B., J. J.] and Urology [R. F., M. K.], Indiana University School of Medicine, 702 Barnhill Drive, Indianapolis, Indiana 46202

The DNA base excision repair pathway is responsible for the repair of cellular alkylation and oxidative DNA damage. A crucial step in the BER pathway involves the cleavage of baseless sites in DNA by an apurinic/apyrimidinic or baseless (AP) endonuclease (Ape1/ref-1), which is a multifunctional enzyme that acts not only as an AP endonuclease but also as a redox-modifying factor for a variety of transcription factors including Fos, Jun, paired box containing genes (PAX), nuclear factor-{kappa}B, hypoxia-inducible factor {alpha} (HIF-1{alpha}), HIF-like factor (HLF), p53, and others. The expression of Ape1/ref-1 in prostate has not been characterized previously. Ape1/ref-1 nuclear immunohistochemistry levels, scored for intensity as 1+, 2+, or 3+, were 91, 3, and 6% in benign hypertrophy (BPH), 0, 42, and 58% in prostatic intraepithelial neoplasia (PIN) and 3, 30, and 67% in prostate cancer, respectively, clearly showing an increase in Ape1/ref-1 nuclear staining in the PIN and cancer compared with BPH. Furthermore, the level of cytoplasmic staining of Ape1/ref-1 in cancer and PIN were elevated (42 and 36%, respectively) compared with BPH (5%). There was no correlation with prostate-specific antigen values or doubling times to Ape1/ref-1 levels. In conclusion, we have demonstrated that Ape1/ref-1 is dramatically elevated in prostate cancer, the level of staining of Ape1/ref-1 increases from low in BPH to intense in PIN and cancer, and there is an increase in the amount of Ape1/ref-1 in the cytoplasm of PIN and cancer compared with BPH. Given these results, we conclude that Ape1/ref-1 may be a diagnostic marker for early prostate cancer and play a role, through its repair, redox, or both functions, in the physiology of the early development of prostate cancer.




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