Resveratrol inhibits development of colorectal adenoma via suppression of LEF1; comprehensive analysis with connectivity map. Issue 12 (20th September 2022)

• Record Type: Journal Article
• Authors: Wada, Hironori; Sato, Yasushi; Fujimoto, Shota; Okamoto, Koichi; Bando, Masahiro; Kawaguchi, Tomoyuki; Miyamoto, Hiroshi; Muguruma, Naoki; Horimoto, Katsuhisa; Matsuzawa, Yui; Mutoh, Michihiro; Takayama, Tetsuji
• Is Part Of: Cancer science. Volume 113:Issue 12(2022)
• Page Start: 4374
• Page End: 4384
• Publication Date: 2022-09-20
• Subjects: chemoprevention -- colorectal adenoma -- connectivity map -- LEF1 -- resveratrol; Cancer -- Periodicals; Neoplasms -- Periodicals; Research -- Periodicals; Electronic journals; 616.994005
• DOI: 10.1111/cas.15576
• Languages: English
• ISSNs: 1347-9032

Abstract

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 Apc Min/+ 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. Abstract : Resveratrol was identified as the most effective compound for chemoprevention against colorectal adenoma comprehensively from 1309 FDA‐approved compounds using connectivity map analysis and in vitro screening of patient‐derived organoids of colorectal adenoma. Resveratrol effectively inhibited development of colorectal adenoma in Apc‐deficient mice and in chemically carcinogenesis rat models by suppressing the expression of LEF1 in the Wnt signaling pathway.