Metformin and Niclosamide Synergistically Suppress Wnt and YAP in APC-Mutated Colorectal Cancer
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 th...
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| Veröffentlicht in: | Cancers 2021-07, Vol.13 (14), p.3437 |
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| creator | Kang, Hee Eun Seo, Yoojeong Yun, Jun Seop Song, Sang Hyun Han, Dawool Cho, Eunae Sandra Cho, Sue Bean Jeon, Yoon Lee, Ho Kim, Hyun Sil Kang, Joyeon Yook, Jong In Kim, Nam Hee Kim, Tae Il |
| description | 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. |
| doi_str_mv | 10.3390/cancers13143437 |
| format | Article |
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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.</description><identifier>ISSN: 2072-6694</identifier><identifier>EISSN: 2072-6694</identifier><identifier>DOI: 10.3390/cancers13143437</identifier><identifier>PMID: 34298652</identifier><language>eng</language><publisher>Basel: MDPI AG</publisher><subject>Adenomatous polyposis coli ; Animal models ; Cancer ; Colorectal cancer ; Colorectal carcinoma ; Gene expression ; Kinases ; Metformin ; Niclosamide ; Oral administration ; Organoids ; Phosphorylation ; Polyposis ; Proteins ; Tumorigenesis ; Wnt protein ; Yes-associated protein</subject><ispartof>Cancers, 2021-07, Vol.13 (14), p.3437</ispartof><rights>2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2021 by the authors. 2021</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c398t-a088ab230c7240559d75636baf0061a8463fb666f05caac90ce4b746c2c3e3433</citedby><cites>FETCH-LOGICAL-c398t-a088ab230c7240559d75636baf0061a8463fb666f05caac90ce4b746c2c3e3433</cites><orcidid>0000-0002-7318-6112 ; 0000-0002-0820-3019 ; 0000-0002-0256-7727 ; 0000-0003-3614-1764 ; 0000-0002-3087-5276 ; 0000-0003-2203-313X ; 0000-0001-5573-742X ; 0000-0003-4807-890X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8308039/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8308039/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids></links><search><creatorcontrib>Kang, Hee Eun</creatorcontrib><creatorcontrib>Seo, Yoojeong</creatorcontrib><creatorcontrib>Yun, Jun Seop</creatorcontrib><creatorcontrib>Song, Sang Hyun</creatorcontrib><creatorcontrib>Han, Dawool</creatorcontrib><creatorcontrib>Cho, Eunae Sandra</creatorcontrib><creatorcontrib>Cho, Sue Bean</creatorcontrib><creatorcontrib>Jeon, Yoon</creatorcontrib><creatorcontrib>Lee, Ho</creatorcontrib><creatorcontrib>Kim, Hyun Sil</creatorcontrib><creatorcontrib>Kang, Joyeon</creatorcontrib><creatorcontrib>Yook, Jong In</creatorcontrib><creatorcontrib>Kim, Nam Hee</creatorcontrib><creatorcontrib>Kim, Tae Il</creatorcontrib><title>Metformin and Niclosamide Synergistically Suppress Wnt and YAP in APC-Mutated Colorectal Cancer</title><title>Cancers</title><description>The Wnt and Hippo pathways are tightly coordinated and understanding their reciprocal regulation may provide a novel therapeutic strategy for cancer. 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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.</description><subject>Adenomatous polyposis coli</subject><subject>Animal models</subject><subject>Cancer</subject><subject>Colorectal cancer</subject><subject>Colorectal carcinoma</subject><subject>Gene expression</subject><subject>Kinases</subject><subject>Metformin</subject><subject>Niclosamide</subject><subject>Oral administration</subject><subject>Organoids</subject><subject>Phosphorylation</subject><subject>Polyposis</subject><subject>Proteins</subject><subject>Tumorigenesis</subject><subject>Wnt protein</subject><subject>Yes-associated protein</subject><issn>2072-6694</issn><issn>2072-6694</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNpdkU1r3DAQhkVpScI251wNufTirKyRZPsSWEyTBpI2kJbSkxjLcqogSxtJDuy_r_NBaDKXGZhn3pmXIeSooicALV1r9NrEVEHFgUP9gRwwWrNSypZ__K_eJ4cp3dElAKpa1ntkHzhrGynYAVFXJo8hTtYX6Ifiu9UuJJzsYIqbnTfx1qZsNTq3K27m7TaalIrfPj_BfzbXxTK3ue7KqzljNkPRBRei0Rld0T1d95l8GtElc_iSV-TX2def3bfy8sf5Rbe5LDW0TS6RNg32DKiuGadCtEMtJMgeR0plhQ2XMPZSypEKjahbqg3vay4102AW87Aip8-627mfzKCNzxGd2kY7YdypgFa97Xj7V92GB9UAbSi0i8CXF4EY7meTspps0sY59CbMSTEhREVBLMtW5Pgdehfm6Bd7jxTnkrY1W6j1M6VjSCma8fWYiqrH_6l3_4N_Z9GNkA</recordid><startdate>20210709</startdate><enddate>20210709</enddate><creator>Kang, Hee Eun</creator><creator>Seo, Yoojeong</creator><creator>Yun, Jun Seop</creator><creator>Song, Sang Hyun</creator><creator>Han, Dawool</creator><creator>Cho, Eunae Sandra</creator><creator>Cho, Sue Bean</creator><creator>Jeon, Yoon</creator><creator>Lee, Ho</creator><creator>Kim, Hyun Sil</creator><creator>Kang, Joyeon</creator><creator>Yook, Jong In</creator><creator>Kim, Nam Hee</creator><creator>Kim, Tae Il</creator><general>MDPI AG</general><general>MDPI</general><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7T5</scope><scope>7TO</scope><scope>7XB</scope><scope>8FE</scope><scope>8FH</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>COVID</scope><scope>DWQXO</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>LK8</scope><scope>M2O</scope><scope>M7P</scope><scope>MBDVC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-7318-6112</orcidid><orcidid>https://orcid.org/0000-0002-0820-3019</orcidid><orcidid>https://orcid.org/0000-0002-0256-7727</orcidid><orcidid>https://orcid.org/0000-0003-3614-1764</orcidid><orcidid>https://orcid.org/0000-0002-3087-5276</orcidid><orcidid>https://orcid.org/0000-0003-2203-313X</orcidid><orcidid>https://orcid.org/0000-0001-5573-742X</orcidid><orcidid>https://orcid.org/0000-0003-4807-890X</orcidid></search><sort><creationdate>20210709</creationdate><title>Metformin and Niclosamide Synergistically Suppress Wnt and YAP in APC-Mutated Colorectal Cancer</title><author>Kang, Hee Eun ; 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| subjects | Adenomatous polyposis coli Animal models Cancer Colorectal cancer Colorectal carcinoma Gene expression Kinases Metformin Niclosamide Oral administration Organoids Phosphorylation Polyposis Proteins Tumorigenesis Wnt protein Yes-associated protein |
| title | Metformin and Niclosamide Synergistically Suppress Wnt and YAP in APC-Mutated Colorectal Cancer |
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