Journal article
Alterations in the expression of the apurinic/apyrimidinic endonuclease-1/redox factor-1 (APE/Ref-1) in human melanoma and identification of the therapeutic potential of resveratrol as an APE/Ref-1 inhibitor
Molecular cancer therapeutics, Vol.4(12), pp.1923-1935
12/2005
DOI: 10.1158/1535-7163.MCT-05-0229
PMID: 16373707
Abstract
Apurinic/apyrimidinic endonuclease-1/redox factor-1 (APE/Ref-1) is a multifunctional protein involved in DNA base excision repair and redox regulation of many transcription factors. In different melanoma cell lines, we found that both nucleus and cytoplasm exhibited higher levels of Ref-1 compared with normal melanocytes. Similar increases of Ref-1 expression, detected by immunohistofluorescence, were also evident in nevi and malignant melanoma biopsies compared with normal skin, which were predominantly localized in the nucleus. Using recombinant adenovirus Adref-1, encoding full-length Ref-1, we transiently overexpressed APE/Ref-1 in human melanocytes, which protected these cells from UVB-induced apoptosis and increased foci formation in culture. Ref-1 overexpression also protected melanoma cells from cisplatin- or H2O2-induced apoptosis, whereas increased apoptosis was observed with Ref-1 antisense construct infection. These observations suggested that intracellular Ref-1 levels played an important role in sensitization of melanoma cells to apoptosis. Electrophoretic mobility shift assay results showed that in both cultured primary and metastatic melanomas DNA-binding activities of activator protein-1 and nuclear factor-kappaB were significantly diminished or shifted when anti-APE/Ref-1 antibody was added to deplete APE/Ref-1 from the binding complexes. Induced nuclear factor-kappaB transcriptional activities were also evident after Ref-1 overexpression. Furthermore, using three-dimensional molecular structure modeling and virtual screening, we found that resveratrol, a natural compound found in fruits and vegetables, docks into a druggable pocket of Ref-1 protein. In vitro studies revealed that resveratrol inhibited, in a dose-dependent manner, Ref-1-activated activator protein-1 DNA-binding activities as well as Ref-1 endonuclease activities and rendered melanoma cells more sensitive to dacarbazine treatment.
Details
- Title: Subtitle
- Alterations in the expression of the apurinic/apyrimidinic endonuclease-1/redox factor-1 (APE/Ref-1) in human melanoma and identification of the therapeutic potential of resveratrol as an APE/Ref-1 inhibitor
- Creators
- Sun Yang - Chao Family Comprehensive Cancer Center and Department of Medicine, University of California-Irvine School of Medicine, Orange, CA 92868, USAKaikobad IraniSusan E HeffronFrances JurnakFrank L Meyskens Jr
- Resource Type
- Journal article
- Publication Details
- Molecular cancer therapeutics, Vol.4(12), pp.1923-1935
- Publisher
- United States
- DOI
- 10.1158/1535-7163.MCT-05-0229
- PMID
- 16373707
- ISSN
- 1535-7163
- eISSN
- 1538-8514
- Grant note
- R01 HL070929 / NHLBI NIH HHS P30-CA62203 / NCI NIH HHS
- Language
- English
- Date published
- 12/2005
- Academic Unit
- Cardiovascular Medicine; Radiation Oncology; Internal Medicine
- Record Identifier
- 9984047761402771
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