1. Resveratrol-induced apoptosis is mediated by early growth response-1, Krüppel-like factor 4, and activating transcription factor 3.
- Author
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Whitlock NC, Bahn JH, Lee SH, Eling TE, and Baek SJ
- Subjects
- Base Sequence, Binding Sites, Blotting, Western, Cell Line, Tumor, Cell Proliferation drug effects, Chromatin Immunoprecipitation, Colorectal Neoplasms genetics, Colorectal Neoplasms pathology, Early Growth Response Protein 1 metabolism, Electrophoretic Mobility Shift Assay, Humans, Immunoenzyme Techniques, Immunoprecipitation, Kruppel-Like Factor 4, Kruppel-Like Transcription Factors metabolism, Luciferases metabolism, Molecular Sequence Data, Phosphorylation drug effects, Promoter Regions, Genetic genetics, Protein Binding, RNA, Messenger genetics, Resveratrol, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Transcriptional Activation, Activating Transcription Factor 3 metabolism, Anticarcinogenic Agents therapeutic use, Apoptosis drug effects, Colorectal Neoplasms drug therapy, Early Growth Response Protein 1 genetics, Kruppel-Like Transcription Factors genetics, Stilbenes therapeutic use
- Abstract
Resveratrol, a dietary phytoalexin readily available in the diet, is reported to possess antitumorigenic properties in several cancers, including colorectal. However, the underlying mechanism(s) involved is not completely understood. In the present study, we investigated the effect of resveratrol treatment on gene modulation in human colorectal cancer cells and identified activating transcription factor 3 (ATF3) as the most highly induced gene after treatment. We confirmed that resveratrol upregulates ATF3 expression, both at the mRNA and protein level, and showed resveratrol involvement in ATF3 transcriptional regulation. Analysis of the ATF3 promoter revealed the importance of early growth response-1 (Egr-1; located at -245 to -236) and Krüppel-like factor 4 (KLF4; located at -178 to -174) putative binding sites in resveratrol-mediated ATF3 transactivation. Specificity of these sites to the Egr-1 and KLF4 protein was confirmed by electrophoretic mobility shift and chromatin immunoprecipitation assays. Resveratrol increased Egr-1 and KLF4 expression, which preceded ATF3 expression, and further suggests Egr-1 and KLF4 involvement in resveratrol-mediated activity. We provide evidence for Egr-1 and KLF4 interaction in the presence of resveratrol, which may facilitate ATF3 transcriptional regulation by this compound. Furthermore, we demonstrate that induction of apoptosis by resveratrol is mediated, in part, by increased ATF3 expression. Taken together, these results provide a novel mechanism by which resveratrol induces ATF3 expression and represent an additional explanation of how resveratrol exerts its antitumorigenic effects in human colorectal cancer cells., (©2011 AACR.)
- Published
- 2011
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