| ORIGINAL ARTICLES |
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Cepharanthine suppresses APC-mutant colorectal cancers by down-regulating the expression of β-catenin |
| Guifeng Su1,2,3, Dan Wang2, Qianqing Yang2, Lingmei Kong2, Xiaoman Ju1,3, Qihong Yang1,3, Yiying Zhu2, Shaohua Zhang2, Yan Li2 |
1. State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, People's Republic of China;
2. Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Key Laboratory of Research and Development for Natural Products, School of Pharmacy, Yunnan University, Kunming, 650500, People's Republic of China;
3. University of Chinese Academy of Sciences, Beijing, 100049, People's Republic of China |
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Abstract The aberrant activation of the Wnt/β-catenin signaling pathway is closely associated with the development of various carcinomas, especially colorectal cancers (CRCs), where adenomatous colorectal polyposis (APC) mutations are the most frequently observed, which limits the anti-tumor efficiency of inhibitors targeting the upstream of Wnt/β-catenin pathway. The anti-tumor activity of the naturally occurring alkaloid cepharanthine (CEP) extracted from the plant Stephania cepharantha Hayata has been reported in various types of tumors. We previously observed that its derivatives inhibited the Wnt/β-catenin signaling in liver cancer; however, the specific mechanism remains unknown. In this study, we confirmed CEP can effectively inhibit APC-mutant CRC cell lines (SW480, SW620, LoVo) through disturbing of the Wnt/β-catenin signaling and elucidated the underlying mechanisms. Here, we demonstrate that CEP attenuates the Wnt/β-catenin signaling by decreasing the β-catenin, subsequently impeding the proliferation of APC-mutant CRCs. Moreover, CEP induced β-catenin transcription inhibition rather than the instability of β-catenin protein and mRNA contributes to reduction of β-catenin. Taken together, our findings identify CEP as the first β-catenin transcriptional inhibitor in the modulation of Wnt/β-catenin signaling and indicate CEP as a potential therapeutic option for the treatment of APC-mutated CRCs.
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| Keywords
Colorectal cancer
Wnt/β-catenin
APC
CEP
Transcriptional inhibitor
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| Fund:This study was funded by the National Natural Science Foundation of China (No. 32260159, 82360725), the Applied Basic Research Foundation of Yunnan Provincet (202301AS070022), Yunnan University (start-up grant to Y.L. and L.K.), the Yunnan Young & Elite Talents Project (YNWR-QNBJ-2020-084), the Central Guidance on Local Science and Technology Development Fund of Yunnan Province (202207AB110002), National Key R&D Program of China (2019YFE0109200), the central government guides local science and technology development fund (202207AA110007). |
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Corresponding Authors:
Yan Li,E-mail:yan.li@ynu.edu.cn
E-mail: yan.li@ynu.edu.cn
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Issue Date: 16 May 2024
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