Artesunate inhibits intestinal tumorigenesis through inhibiting wnt signaling

Takahiro Hamoya; Gen Fujii; Yosuke Iizumi; Takumi Narita; Masami Komiya; Yui Matsuzawa; Kohei Miki; Tadashi Kondo; Shinji Kishimoto; Kenji Watanabe; Keiji Wakabayashi; Toshiyuki Sakai; Jiro Toshima; Michihiro Mutoh

doi:10.1093/carcin/bgaa084

Artesunate inhibits intestinal tumorigenesis through inhibiting wnt signaling

Carcinogenesis. 2021 Feb 11;42(1):148-158. doi: 10.1093/carcin/bgaa084.

Authors

Takahiro Hamoya^{1

2

3}, Gen Fujii⁴, Yosuke Iizumi¹, Takumi Narita^{1

2}, Masami Komiya², Yui Matsuzawa^{2

3}, Kohei Miki^{2

3}, Tadashi Kondo⁵, Shinji Kishimoto⁶, Kenji Watanabe⁶, Keiji Wakabayashi⁷, Toshiyuki Sakai⁸, Jiro Toshima³, Michihiro Mutoh^{1

2

3

9}

Affiliations

¹ Department of Molecular-Targeting Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, Japan.
² Epidemiology and Prevention Division, Research Center for Cancer Prevention and Screening, National Cancer Center, Tsukiji, Chuo-ku, Tokyo, Japan.
³ Department of Biological Science and Technology, Tokyo University of Science, Niijuku, Katsushika-ku, Tokyo, Japan.
⁴ Central Radioisotope Division, National Cancer Center Research Institute, Tsukiji, Chuo-ku, Tokyo, Japan.
⁵ Division of Rare Cancer Research, National Cancer Center Research Institute, Tsukiji, Chuo-ku, Tokyo, Japan.
⁶ Department of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
⁷ Graduate Division of Nutritional and Environmental Sciences, University of Shizuoka, Shizuoka, Japan.
⁸ Department of Drug Discovery Medicine, Drug Discovery Center, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, Japan.
⁹ Division of Carcinogenesis and Cancer Prevention, National Cancer Center Research Institute, Tsukiji, Chuo-ku, Tokyo, Japan.

PMID: 32710739
DOI: 10.1093/carcin/bgaa084

Abstract

Artesunate (ART) is a clinically approved antimalarial drug and was revealed as a candidate of colorectal cancer chemopreventive agents in our drug screening system. Here, we aimed to understand the suppressive effects of ART on intestinal tumorigenesis. In vitro, ART reduced T-cell factor/lymphoid enhancer factor (TCF/LEF) promoter transcriptional activity. In vivo, ART inhibited intestinal polyp development. We found that ART reduces TCF1/TCF7 nuclear translocation by binding the Ras-related nuclear protein (RAN), suggesting that ART inhibits TCF/LEF transcriptional factor nuclear translocation by binding to RAN, thereby inhibiting Wnt signaling. Our results provide a novel mechanism through which artesunate inhibits intestinal tumorigenesis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenomatous Polyposis Coli / genetics
Adenomatous Polyposis Coli / pathology
Adenomatous Polyposis Coli / prevention & control*
Adenomatous Polyposis Coli Protein / genetics
Animals
Artesunate / pharmacology*
Artesunate / therapeutic use
Carcinogenesis / drug effects*
Cell Line, Tumor
Cell Nucleus / metabolism
Disease Models, Animal
Drug Evaluation, Preclinical
Gene Expression Regulation, Neoplastic / drug effects*
Gene Knockdown Techniques
Hepatocyte Nuclear Factor 1-alpha / genetics
Hepatocyte Nuclear Factor 1-alpha / metabolism
Humans
Intestinal Mucosa / drug effects
Intestinal Mucosa / pathology
Male
Mice
Mice, Transgenic
Mutation
Promoter Regions, Genetic
T Cell Transcription Factor 1 / genetics
T Cell Transcription Factor 1 / metabolism
Transcriptional Activation / drug effects
Wnt Signaling Pathway / drug effects*
Wnt Signaling Pathway / genetics
ran GTP-Binding Protein / antagonists & inhibitors
ran GTP-Binding Protein / genetics
ran GTP-Binding Protein / metabolism

Substances

Adenomatous Polyposis Coli Protein
HNF1A protein, human
Hepatocyte Nuclear Factor 1-alpha
Hnf1a protein, mouse
RAN protein, human
Ran protein, mouse
T Cell Transcription Factor 1
TCF7 protein, human
adenomatous polyposis coli protein, mouse
Artesunate
ran GTP-Binding Protein