Alterations in activating protein 1 composition correlate with phenotypic differentiation changes induced by resveratrol in human melanoma.
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 H(2)O(2) (10 muM) partially reversed the inhibition of colony proliferation; however, no effects on either MHC class I antigen or Fas expression was evident. Although H(2)O(2) restored participation of c-Jun in AP-1 complexes, H(2)O(2) 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.
Yang
Sun
S
College of Medicine, University of California-Irvine, 101 The City Drive South, Bldg. 56, Room 215, Orange, CA 92868, USA.
Meyskens
Frank L
FL
D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects*; D002460:Cell Line; D045744:Cell Line, Tumor; D006801:Humans; D007231:Infant, Newborn; D008544:Melanocytes; D008545:Melanoma / Q000235:genetics / Q000473:pathology*; D010641:Phenotype; D017382:Reactive Oxygen Species / Q000378:metabolism; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000737:chemistry* / Q000235:genetics*; D014158:Transcription, Genetic
D000975:Antioxidants; D017382:Reactive Oxygen Species; D013267:Stilbenes; D018808:Transcription Factor AP-1; D013755:Tetradecanoylphorbol Acetate; D000077185:Resveratrol