Abstract
Resveratrol (trans-3,4',5-trihydroxystilbene) is a naturally occurring polyphenolic phytoalexin found in grapes, and has been shown to inhibit the growth of various types of cancer cells. We investigated the mechanism of the antiproliferative effect of resveratrol in A431-transformed keratinocytes harbouring mutant p53, and show that it is accompanied by G1 cell cycle arrest, which coincides with a marked inhibition of G1 cell cycle regulatory proteins, including cyclins A and D1 and cyclin-dependent kinase (CDK)6 and p53-independent induction of p21WAF1. Cell cycle arrest was also associated with the accumulation of hypophosphorylated Rb and p27KIP1. Resveratrol inhibited mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK)1 > extracellular signal-regulated protein kinase (ERK)1/2 signalling, downregulated c-Jun, and suppressed activating protein (AP)-1 DNA-binding and promoter activity. In addition, the inhibition of MEK1 > ERK1/2 signalling appears to be independent of retinoblastoma protein (pRb) hypophosphorylation in A431 cells, as PD098059 did not suppress pRb phosphorylation. Our results demonstrate that resveratrol affects multiple cellular targets in A431 cells, and that the downregulation of both AP-1 and pRb contributes to its antiproliferative activity in these cells.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Antineoplastic Agents, Phytogenic / pharmacology
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Blotting, Western
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Carcinoma, Squamous Cell / metabolism
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Carcinoma, Squamous Cell / pathology
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Cell Cycle / drug effects
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism
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Cell Line, Tumor
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Cell Proliferation / drug effects*
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Cell Survival / drug effects
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DNA-Binding Proteins / chemistry
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DNA-Binding Proteins / metabolism
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Dimerization
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Dose-Response Relationship, Drug
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Flavonoids / pharmacology
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Gene Expression / drug effects
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Humans
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MAP Kinase Kinase 1 / metabolism*
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Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 3 / metabolism
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Phosphorylation / drug effects
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Protein Binding / drug effects
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Proto-Oncogene Proteins c-jun / metabolism
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Resveratrol
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Signal Transduction / drug effects*
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Stilbenes / pharmacology*
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Transcription Factor AP-1 / chemistry
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Transcription Factor AP-1 / metabolism*
Substances
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Antineoplastic Agents, Phytogenic
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Cell Cycle Proteins
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DNA-Binding Proteins
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Flavonoids
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Proto-Oncogene Proteins c-jun
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RNA, Messenger
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Stilbenes
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Transcription Factor AP-1
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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MAP Kinase Kinase 1
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MAP2K1 protein, human
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Resveratrol
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2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one