Document Detail

Alterations in activating protein 1 composition correlate with phenotypic differentiation changes induced by resveratrol in human melanoma.
MedLine Citation:
PMID:  15492115     Owner:  NLM     Status:  MEDLINE    
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.
Sun Yang; Frank L Meyskens
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.     Date:  2004-10-18
Journal Detail:
Title:  Molecular pharmacology     Volume:  67     ISSN:  0026-895X     ISO Abbreviation:  Mol. Pharmacol.     Publication Date:  2005 Jan 
Date Detail:
Created Date:  2004-12-23     Completed Date:  2005-03-28     Revised Date:  2013-06-03    
Medline Journal Info:
Nlm Unique ID:  0035623     Medline TA:  Mol Pharmacol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  298-308     Citation Subset:  IM    
College of Medicine, University of California-Irvine, 101 The City Drive South, Bldg. 56, Room 215, Orange, CA 92868, USA.
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MeSH Terms
Antioxidants / pharmacology
Apoptosis / drug effects*
Cell Cycle / drug effects*
Cell Line
Cell Line, Tumor
Infant, Newborn
Melanoma / genetics,  pathology*
Reactive Oxygen Species / metabolism
Stilbenes / pharmacology*
Tetradecanoylphorbol Acetate / pharmacology
Transcription Factor AP-1 / chemistry*,  genetics*
Transcription, Genetic
Grant Support
Reg. No./Substance:
0/Antioxidants; 0/Reactive Oxygen Species; 0/Stilbenes; 0/Transcription Factor AP-1; 16561-29-8/Tetradecanoylphorbol Acetate; Q369O8926L/resveratrol

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