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Metformin and Niclosamide Synergistically Suppress Wnt and YAP in APC-Mutated Colorectal Cancer

Authors
 Hee Eun Kang  ;  Yoojeong Seo  ;  Jun Seop Yun  ;  Sang Hyun Song  ;  Dawool Han  ;  Eunae Sandra Cho  ;  Sue Bean Cho  ;  Yoon Jeon  ;  Ho Lee Hyun Sil Kim  ;  Joyeon Kang  ;  Jong In Yook  ;  Nam Hee Kim  ;  Tae Il Kim 
Citation
 CANCERS, Vol.13(14) : 3437, 2021-07 
Journal Title
CANCERS
Issue Date
2021-07
Keywords
Hippo ; Wnt ; colorectal cancer ; metformin ; niclosamide
Abstract
The Wnt and Hippo pathways are tightly coordinated and understanding their reciprocal regulation may provide a novel therapeutic strategy for cancer. Anti-helminthic niclosamide is an effective inhibitor of Wnt and is now in a phase II trial for advanced colorectal cancer (CRC) patients. We found that Axin2, an authentic target gene of canonical Wnt, acts as aYAP phosphorylation activator in APC-mutated CRC. While niclosamide effectively suppresses Wnt, it also inhibits Hippo, limiting its therapeutic potential for CRC. To overcome this limitation, we utilized metformin, a clinically available AMPK activator. This combinatory approach not only suppresses canonical Wnt activity, but also inhibits YAP activity in CRC cancer cells and in patient-derived cancer organoid through the suppression of cancer stemness. Further, combinatory oral administration suppressed in vivo tumorigenesis and the cancer progression of APC-MIN mice models. Our observations provide not only a reciprocal link between Wnt and Hippo, but also clinically available novel therapeutics that are able to target Wnt and YAP in APC-mutated CRC.
Files in This Item:
T202102760.pdf Download
DOI
10.3390/cancers13143437
Appears in Collections:
2. College of Dentistry (치과대학) > Research Institute (부설연구소) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
2. College of Dentistry (치과대학) > Dept. of Oral Pathology (구강병리학교실) > 1. Journal Papers
Yonsei Authors
Kim, Nam Hee(김남희) ORCID logo https://orcid.org/0000-0002-3087-5276
Kim, Tae Il(김태일) ORCID logo https://orcid.org/0000-0003-4807-890X
Kim, Hyun Sil(김현실) ORCID logo https://orcid.org/0000-0003-3614-1764
Yook, Jong In(육종인) ORCID logo https://orcid.org/0000-0002-7318-6112
Cho, Eunae(조은애산드라) ORCID logo https://orcid.org/0000-0002-0820-3019
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/184298
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