Received for publication August 18, 2004.
Revised October 1, 2004.
Accepted for publication October 5, 2004.

Alterations in activating protein 1 (AP-1) composition correlate with phenotypic differentiation changes induced by resveratrol in human melanoma

Abstract

Resveratrol has demonstrated preventive and therapeutic activities in a wide 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, while even at high doses no distinct apoptosis or cell cycle arrest was observed. Notably, c83-2c (metastatic) and wm3211 (radial growth phase) melanoma cells became more dendritic-shaped with resveratrol treatment. 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 AP-1 (activator protein-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. Further, we overexpressed Fra-2 in human melanoma cells using a Fra-2 expression construct and both AP-1 transcriptional activity and TPA-induced transcriptional transactivation were reduced significantly, while MHC class I antigen and Fas/CD95 levels were elevated to 2.0- and 1.8-times of control respectively. Addition of H₂O₂ (10µM) partially reversed the inhibition of colony proliferation; however, no effects on either MHC class I antigen or Fas expression were 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 ROS levels, substantially contribute to the phenotypic changes induced by resveratrol.

Key words: AP-1, Oxidative stress/antioxidants, Transcription targets

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