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Updated: Aug 29, 2025
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Published on: September 3, 2021
Resveratrol inhibits development of colorectal adenoma via suppression of LEF1; comprehensive analysis with
Hironori Wada1, Yasushi Sato2, Shota Fujimoto1
1Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
Abstract:
Although many chemopreventive studies on colorectal tumors have been reported, no effective and safe preventive agent is currently available. We searched for candidate preventive compounds against colorectal tumor comprehensively from United States Food and Drug Administration (FDA)-approved compounds by using connectivity map (CMAP) analysis coupled with in vitro screening with colorectal adenoma (CRA) patient-derived organoids (PDOs). We generated CRA-specific gene signatures based on the DNA microarray analysis of CRA and normal epithelial specimens, applied them to CMAP analysis with 1309 FDA-approved compounds, and identified 121 candidate compounds that should cancel the gene signatures. We narrowed them down to 15 compounds, and evaluated their inhibitory effects on the growth of CRA-PDOs in vitro. We finally identified resveratrol, one of the polyphenolic phytochemicals, as a compound showing the strongest inhibitory effect on the growth of CRA-PDOs compared with normal epithelial PDOs. When resveratrol was administered to ApcMin/+ mice at 15 or 30 mg/kg, the number of polyps (adenomas) was significantly reduced in both groups compared with control mice. Similarly, the number of polyps (adenomas) was significantly reduced in azoxymethane-injected rats treated with 10 or 100 mg/resveratrol compared with control rats. Microarray analysis of adenomas from resveratrol-treated rats revealed the highest change (downregulation) in expression of LEF1, a key molecule in the Wnt signaling pathway. Treatment with resveratrol significantly downregulated the Wnt-target gene (MYC) in CRA-PDOs. Our data demonstrated that resveratrol can be the most effective compound for chemoprevention of colorectal tumors, the efficacy of which is mediated through suppression of LEF1 expression in the Wnt signaling pathway.
Insights
Resveratrol effectively prevents colorectal tumors by inhibiting polyp growth in preclinical models. This polyphenol suppresses key Wnt signaling pathway genes, offering a promising chemopreventive strategy for colorectal cancer.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Despite numerous chemoprevention studies, no universally effective and safe agent for colorectal tumors currently exists.
- Identifying novel therapeutic compounds is crucial for managing and preventing colorectal cancer progression.
Purpose of the Study:
- To identify effective chemopreventive agents for colorectal tumors from FDA-approved compounds.
- To investigate the efficacy of candidate compounds in preclinical models and elucidate their mechanism of action.
Main Methods:
- Utilized Connectivity Map (CMAP) analysis with colorectal adenoma (CRA)-specific gene signatures to screen 1309 FDA-approved compounds.
- Performed in vitro screening using colorectal adenoma patient-derived organoids (PDOs) and in vivo studies in ApcMin/+ mice and azoxymethane-injected rats.
- Analyzed gene expression changes, focusing on the Wnt signaling pathway, in response to treatment.
Main Results:
- Identified 121 candidate compounds, narrowing down to 15 for in vitro evaluation.
- Resveratrol demonstrated the strongest inhibitory effect on CRA-PDO growth compared to normal organoids.
- Resveratrol significantly reduced polyp formation in mouse and rat models and downregulated LEF1 and MYC expression in the Wnt pathway.
Conclusions:
- Resveratrol is a highly effective compound for colorectal tumor chemoprevention.
- Its efficacy is attributed to the suppression of LEF1 expression within the Wnt signaling pathway.
- Resveratrol represents a promising therapeutic candidate for preventing colorectal tumors.
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