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 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-kappaB, hypoxia-inducible factor alpha (HIF-1alpha), 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.
Kelley
M R
MR
Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, 702 Barnhill Drive, Indianapolis, Indiana 46202, USA. mkelley@iupui.edu
Cheng
L
L
Foster
R
R
Tritt
R
R
Jiang
J
J
Broshears
J
J
Koch
M
M
D014408:Biomarkers, Tumor / Q000378:metabolism*; D019757:Carbon-Oxygen Lyases / Q000378:metabolism*; D011088:DNA Ligases / Q000378:metabolism*; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D006801:Humans; D008297:Male; D015513:Oncogene Proteins / Q000378:metabolism; D010084:Oxidation-Reduction; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000175:diagnosis / Q000201:enzymology* / Q000378:metabolism; D014407:Tumor Cells, Cultured
D014408:Biomarkers, Tumor; D015513:Oncogene Proteins; D019757:Carbon-Oxygen Lyases; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D011088:DNA Ligases