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Elevated gadd153/chop expression during resveratrol-induced apoptosis in human colon cancer cells
Kyung Jin Woo1, Tae Jin Lee, Sang Han Lee
1Department of Immunology, School of Medicine, Keimyung University, 194 DongSan-Dong Jung-Gu, Taegu 700-712, South Korea.
Abstract:
Resveratrol (3,4',5-tri-hydroxystilbene), a natural phytoalexin found at high levels in grapes and red wine, has been shown to induce anti-proliferation and apoptosis of human cancer cell lines. Resveratrol-induced dose-dependent apoptotic cell death in colon carcinoma cells, as measured by FACS analysis and internucleosomal DNA fragmentation assays. We demonstrate for the first time that resveratrol induce CCAAT/enhancer-binding protein-homologous protein (CHOP). Resveratrol-induced CHOP mRNA (and also protein) expression was inhibited by JNK specific inhibitor, but not ERK, p38 MAPK, PI3K and NF-kappaB inhibitors. Resveratrol-induced expression of CHOP involves the putative Sp1 site within the CHOP promoter region. Using a combination of the Sp1 cDNA transfection, the luciferase reporter assay and Sp1 inhibitor assay, we found that Sp1 site is required for resveratrol-mediated activation of the CHOP promoter. Suppression of CHOP expression by CHOP siRNA and treatment with mithramycin A attenuated resveratrol-induced apoptosis. Taken together, the present studies suggest that induction of CHOP protein may be involved, at least in part, in resveratrol-induced apoptosis.
Insights
Resveratrol, found in grapes, triggers cancer cell death by inducing CHOP protein. This process involves the Sp1 site and is crucial for resveratrol's apoptotic effects in colon cancer cells.
Area of Science:
- Molecular Biology
- Biochemistry
- Cancer Research
Background:
- Resveratrol is a natural compound found in grapes and red wine.
- It exhibits anti-proliferative and apoptotic effects on human cancer cell lines.
- The precise mechanisms underlying resveratrol-induced apoptosis require further elucidation.
Purpose of the Study:
- To investigate the role of CCAAT/enhancer-binding protein-homologous protein (CHOP) in resveratrol-induced apoptosis.
- To identify the signaling pathways and regulatory elements involved in CHOP induction by resveratrol.
Main Methods:
- Flow cytometry (FACS) and DNA fragmentation assays to measure apoptosis.
- Quantitative real-time PCR and Western blotting to assess CHOP mRNA and protein expression.
- Inhibition studies using specific pathway inhibitors (JNK, ERK, p38 MAPK, PI3K, NF-kappaB).
- Reporter gene assays and site-directed mutagenesis to analyze the role of the Sp1 site in the CHOP promoter.
- RNA interference (siRNA) to suppress CHOP expression.
Main Results:
- Resveratrol induced dose-dependent apoptosis in colon carcinoma cells.
- Resveratrol significantly increased CHOP mRNA and protein expression.
- CHOP induction by resveratrol was specifically inhibited by a JNK inhibitor.
- The Sp1 binding site in the CHOP promoter was essential for resveratrol-mediated activation.
- Suppression of CHOP expression attenuated resveratrol-induced apoptosis.
Conclusions:
- CCAAT/enhancer-binding protein-homologous protein (CHOP) induction is a key mediator of resveratrol-induced apoptosis in colon cancer cells.
- The JNK signaling pathway and the Sp1 transcription factor are critical for resveratrol's effect on CHOP expression.
- These findings highlight a novel mechanism for resveratrol's anti-cancer activity.
