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Alterations in Activating Protein 1 Composition Correlate with Phenotypic Differentiation Changes Induced by Resveratrol in Human Melanoma

Departments of Medicine and Biological Chemistry and Chao Family Comprehensive Cancer Center, University of California, Irvine, Orange, California

Resveratrol has demonstrated preventive and therapeutic activities in a variety of tumors. However, the mechanistic basis of its pharmacological effects on human melanoma has not been well defined. Our results demonstrated that resveratrol significantly inhibited melanoma anchorage-independent growth, and even at high doses no distinct apoptosis or cell cycle arrest was observed. It is noteworthy that c83-2c (metastatic) and wm3211 (radial growth phase) melanoma cells became more dendritic shaped with resveratrol treatment. Major histocompatibility complex (MHC) class I antigen and Fas/CD95 constitutive surface expression levels were, respectively, increased by 2.7- and 1.6-fold of control in c83-2c cells. Resveratrol reduced both activator protein-1 (AP-1) DNA binding and transcriptional activities, and supershift assay revealed that AP-1 composition was shifted from c-Jun/JunD/Fra-1 to JunD/Fra-1/Fra-2, with markedly increased JunD, Fra-1, and Fra-2 protein expression levels in the nucleus. Furthermore, we overexpressed Fra-2 in human melanoma cells by using a Fra-2 expression construct and both AP-1 transcriptional activity and 12-O-tetradecanoylphorbol-induced transcriptional transactivation were reduced significantly, whereas MHC class I antigen and Fas/CD95 levels were elevated to 2.0 and 1.8 times of control, respectively. Addition of H₂O₂ (10 µM) partially reversed the inhibition of colony proliferation; however, no effects on either MHC class I antigen or Fas expression was evident. Although H₂O₂ restored participation of c-Jun in AP-1 complexes, H₂O₂ addition did not affect the induction of Fra-1 and Fra-2 by resveratrol nor the morphological changes. We propose that alterations in AP-1 transcription signaling, mediated by changes in AP-1 dimeric composition and reduced intracellular reactive oxygen species levels, substantially contribute to the phenotypic changes induced by resveratrol.

Address correspondence to: Dr. Frank L. Meyskens, Jr., 101 The City Drive South, Bldg. 56, Room 215, College of Medicine, University of California, Irvine, Orange CA 92868. E-mail: flmeyske{at}uci.edu

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