Elevated and altered expression of the multifunctional DNA base excision repair and redox enzyme Ape1/ref-1 in prostate cancer

The DNA base excision repair pathway is responsible far the repair of cellu lar 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 enzy me that acts not only as an AP endonuclease but also as a redox-modifying f actor for a variety of transcription factors including Fos, Jun, paired box containing genes (PAX), nuclear factor-kappaB, hypoxia-inducible factor al pha (HIF-1 alpha), HIF-like factor (HLF), p53, and others. The expression o f Ape1/ref-1 in prostate has not been characterized previously. Ape1/ref-1 nuclear immunohistochemistry levels, scored for intensity as If, 2+, or 3+, were 91, 3, and 6% in benign hypertrophy: (BPH), 0, 42, and 58% in prostat ic intraepithelial neoplasia (PIN) and 3, 30, and 67% in prostate cancer, r espectively, clearly showing an increase in Ape1/ref-1 nuclear staining in the PLY and cancer compared with BPH. Furthermore, the level of cytoplasmic staining of Ape1/ref-1 in cancer and PIN were elevated (42 and 36%, respec tively) compared,vith BPH (5%). There was no correlation with prostate-spec ific antigen values or doubling times to Ape1/ref-1 levels. In conclusion, we have demonstrated that Ape1/ref-1 is dramatically elevated in prostate c ancer, the level of staining of Ape1/ref-1 increases from low in BPH to int ense 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 t he physiology of the early development of prostate cancer.