Metformin and Niclosamide Synergistically Suppress Wnt and YAP in APC-Mutated Colorectal Cancer.
Hippo
Wnt
colorectal cancer
metformin
niclosamide
Journal
Cancers
ISSN: 2072-6694
Titre abrégé: Cancers (Basel)
Pays: Switzerland
ID NLM: 101526829
Informations de publication
Date de publication:
09 Jul 2021
09 Jul 2021
Historique:
received:
04
05
2021
revised:
05
07
2021
accepted:
06
07
2021
entrez:
24
7
2021
pubmed:
25
7
2021
medline:
25
7
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 34298652
pii: cancers13143437
doi: 10.3390/cancers13143437
pmc: PMC8308039
pii:
doi:
Types de publication
Journal Article
Langues
eng
Subventions
Organisme : National Research Foundation of Korea
ID : NRF-2017M3A9G2074773
Organisme : National Research Foundation of Korea
ID : NRF-2017R1A2B3002241
Organisme : National Research Foundation of Korea
ID : NRF-2018M3A9E2022820
Organisme : National Research Foundation of Korea
ID : NRF-2019R1A2C2084535
Organisme : National Research Foundation of Korea
ID : NRF-2021R1A2C3003496
Références
ACS Infect Dis. 2020 May 8;6(5):909-915
pubmed: 32125140
Nat Cell Biol. 2006 Dec;8(12):1398-406
pubmed: 17072303
PLoS One. 2011;6(12):e29290
pubmed: 22195040
FASEB J. 2015 Feb;29(2):724-32
pubmed: 25384421
Cold Spring Harb Perspect Biol. 2015 Aug 03;7(8):a019141
pubmed: 26238356
Genes Dev. 2010 Nov 1;24(21):2383-8
pubmed: 21041407
Nat Cell Biol. 2015 Apr;17(4):500-10
pubmed: 25751140
Nat Med. 2016 Oct;22(10):1101-1107
pubmed: 27571349
Onco Targets Ther. 2013 Nov 18;6:1685-93
pubmed: 24273411
PLoS One. 2013 Jun 10;8(6):e65539
pubmed: 23762387
J Natl Cancer Inst. 2011 Jul 6;103(13):1018-36
pubmed: 21685359
Cancer Res. 2011 Jun 15;71(12):4172-82
pubmed: 21531761
Eur J Cancer. 2012 May;48(8):1227-34
pubmed: 22056638
Gynecol Oncol. 2014 Jul;134(1):112-20
pubmed: 24736023
Bioorg Med Chem. 2004 May 15;12(10):2517-21
pubmed: 15110833
Clin Cancer Res. 2013 Aug 1;19(15):4124-36
pubmed: 23908450
Cancer Sci. 2010 May;101(5):1279-85
pubmed: 20219076
Proc Natl Acad Sci U S A. 2011 Jul 19;108(29):11930-5
pubmed: 21730131
Genes Dev. 2006 Oct 1;20(19):2687-700
pubmed: 17015431
Mol Cancer Ther. 2014 Apr;13(4):800-11
pubmed: 24552774
Diabetes. 2002 Aug;51(8):2420-5
pubmed: 12145153
Nat Commun. 2018 Jun 12;9(1):2301
pubmed: 29895829
Proc Natl Acad Sci U S A. 2001 Dec 18;98(26):14973-8
pubmed: 11752446
Oncotarget. 2016 Dec 27;7(52):86803-86815
pubmed: 27888804
Mol Cancer Ther. 2013 Oct;12(10):2200-12
pubmed: 23894143
BMC Cancer. 2018 Mar 15;18(1):297
pubmed: 29544454
PLoS One. 2014 May 06;9(5):e96801
pubmed: 24802416
Cancer Sci. 2008 Nov;99(11):2136-41
pubmed: 18803638
Nat Rev Cancer. 2015 Feb;15(2):73-79
pubmed: 25592648
Am J Transl Res. 2017 Aug 15;9(8):3776-3786
pubmed: 28861168
Oncotarget. 2017 May 9;8(19):31842-31855
pubmed: 28418862
Genes Dev. 2015 Jul 15;29(14):1493-506
pubmed: 26193883
Curr Opin Cell Biol. 2008 Dec;20(6):638-46
pubmed: 18955139
Ann Intern Med. 1985 Apr;102(4):550-1
pubmed: 3977200
Cancer Res. 2010 Mar 15;70(6):2516-27
pubmed: 20215516
Antimicrob Agents Chemother. 2004 Jul;48(7):2693-6
pubmed: 15215127
Proc Natl Acad Sci U S A. 2012 Jul 10;109(28):11312-7
pubmed: 22745173
Cell. 2015 Nov 5;163(4):811-28
pubmed: 26544935
Cell. 2012 Jun 8;149(6):1192-205
pubmed: 22682243
Nat Cell Biol. 2015 Apr;17(4):490-9
pubmed: 25751139
Front Cell Dev Biol. 2019 Aug 14;7:156
pubmed: 31475147
Mol Cell Biol. 2002 Feb;22(4):1184-93
pubmed: 11809809
Theranostics. 2021 Mar 31;11(12):5686-5699
pubmed: 33897875
J Biol Chem. 2002 Jun 14;277(24):21657-65
pubmed: 11940574
Cancer Lett. 2014 Jul 10;349(1):8-14
pubmed: 24732808
Eur J Pharmacol. 2018 Sep 5;834:45-53
pubmed: 30017802
Nat Genet. 2000 Oct;26(2):146-7
pubmed: 11017067
Cancer Epidemiol Biomarkers Prev. 2015 Nov;24(11):1692-8
pubmed: 26377195
J Cancer. 2018 Oct 18;9(22):4150-4155
pubmed: 30519314
Cancer Epidemiol Biomarkers Prev. 2018 May;27(5):525-530
pubmed: 29716927