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¹ Chao Family Comprehensive Cancer Center and Departments of ² Medicine and ³ Biological Chemistry, University of California-Irvine School of Medicine, Orange, California; ⁴ Cardiovascular Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; and ⁵ Department of Physiology and Biophysics, University of California-Irvine, Irvine, California

Requests for reprints: Frank L. Meyskens, Jr., University of California-Irvine School of Medicine, Building 56, Room 215, 101 The City Drive South, Orange, CA 92868. Phone: 714-456-6310; Fax: 714-456-2240. E-mail: FLMeyske{at}uci.edu

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-B 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-B 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. [Mol Cancer Ther 2005;4(12):1923–35]

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⁶ S. Yang and F.L. Meyskens, Jr., unpublished observations.

Received 7/ 5/05; revised 8/17/05; accepted 9/21/05.

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