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Cancer Prev Res (Phila)
2013 Dec 01;612:1356-64. doi: 10.1158/1940-6207.CAPR-13-0241.
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Esculetin suppresses proliferation of human colon cancer cells by directly targeting β-catenin.
Lee SY
,
Lim TG
,
Chen H
,
Jung SK
,
Lee HJ
,
Lee MH
,
Kim DJ
,
Shin A
,
Lee KW
,
Bode AM
,
Surh YJ
,
Dong Z
.
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The Wnt pathway is a promising therapeutic and preventive target in various human cancers. The transcriptional complex of β-catenin-T-cell factor (Tcf), a key mediator of canonical Wnt signaling, has been implicated in human colon cancer development. Current treatment of colon cancer depends on traditional cytotoxic agents with limited effects. Therefore, the identification of natural compounds that can disrupt the β-catenin-TcF complex to suppress cancer cell growth with fewer adverse side effects is needed. To identify compounds that inhibit the association between β-catenin and Tcf, we used computer docking to screen a natural compound library. Esculetin, also known as 6,7-dihydroxycoumarin, is a derivative of coumarin and was identified as a potential small-molecule inhibitor of the Wnt-β-catenin pathway. We then evaluated the effect of esculetin on the growth of various human colon cancer cell lines and its effect on Wnt-β-catenin signaling in cells and in an embryonic model. Esculetin disrupted the formation of the β-catenin-Tcf complex through direct binding with the Lys312, Gly307, Lys345, and Asn387 residues of β-catenin in colon cancer cells. In addition, esculetin effectively decreased viability and inhibited anchorage-independent growth of colon cancer cells. Esculetin potently antagonized the cellular effects of β-catenin-dependent activity, and in vivo treatment with esculetin suppressed tumor growth in a colon cancer xenograft mouse model. Our data indicate that the interaction between esculetin and β-catenin inhibits the formation of the β-catenin-Tcf complex, which could contribute to esculetin's positive therapeutic and preventive effects against colon carcinogenesis.
Adfa,
Antitermite activities of coumarin derivatives and scopoletin from Protium javanicum Burm. f.
2010, Pubmed
Adfa,
Antitermite activities of coumarin derivatives and scopoletin from Protium javanicum Burm. f.
2010,
Pubmed
Awaad,
New biological activities of Casimiroa edulis leaf extract and isolated compounds.
2012,
Pubmed
Behrens,
The role of the Wnt signalling pathway in colorectal tumorigenesis.
2005,
Pubmed
Berman,
The Protein Data Bank.
2000,
Pubmed
Bubols,
The antioxidant activity of coumarins and flavonoids.
2013,
Pubmed
Buchert,
Genetic dissection of differential signaling threshold requirements for the Wnt/beta-catenin pathway in vivo.
2010,
Pubmed
Cai,
Antioxidant activity and phenolic compounds of 112 traditional Chinese medicinal plants associated with anticancer.
2004,
Pubmed
Clevers,
Wnt/β-catenin signaling and disease.
2012,
Pubmed
De Robertis,
Dorsal-ventral patterning and neural induction in Xenopus embryos.
2004,
Pubmed
,
Xenbase
Fearnhead,
Genetics of colorectal cancer: hereditary aspects and overview of colorectal tumorigenesis.
2002,
Pubmed
Flaherty,
Wnt signaling and cardiac differentiation.
2012,
Pubmed
Graham,
Crystal structure of a beta-catenin/Tcf complex.
2000,
Pubmed
,
Xenbase
He,
Identification of c-MYC as a target of the APC pathway.
1998,
Pubmed
Herbst,
Wnt signaling as a therapeutic target for cancer.
2007,
Pubmed
Jemal,
Global cancer statistics.
2011,
Pubmed
Kaneko,
Inhibitory effect of natural coumarin compounds, esculetin and esculin, on oxidative DNA damage and formation of aberrant crypt foci and tumors induced by 1,2-dimethylhydrazine in rat colons.
2007,
Pubmed
Kharaishvili,
Wnt signaling in prostate development and carcinogenesis.
2011,
Pubmed
Kikuchi,
Roles of Axin in the Wnt signalling pathway.
1999,
Pubmed
Klaus,
Wnt signalling and its impact on development and cancer.
2008,
Pubmed
Liu,
The third 20 amino acid repeat is the tightest binding site of APC for beta-catenin.
2006,
Pubmed
Logan,
The Wnt signaling pathway in development and disease.
2004,
Pubmed
Luu,
Wnt/beta-catenin signaling pathway as a novel cancer drug target.
2004,
Pubmed
Matsunaga,
Inhibitory effects of nabumetone, a cyclooxygenase-2 inhibitor, and esculetin, a lipoxygenase inhibitor, on N-methyl-N-nitrosourea-induced mammary carcinogenesis in rats.
1998,
Pubmed
Miller,
Mechanism and function of signal transduction by the Wnt/beta-catenin and Wnt/Ca2+ pathways.
1999,
Pubmed
Miller,
Surveillance for diarrheal disease in New York City.
1999,
Pubmed
Miyoshi,
Activation of different Wnt/beta-catenin signaling components in mammary epithelium induces transdifferentiation and the formation of pilar tumors.
2002,
Pubmed
Miyoshi,
Beta-catenin: a transforming actor on many stages.
2003,
Pubmed
Moon,
Teaching resource. Canonical Wnt/beta-catenin signaling.
2004,
Pubmed
Moon,
WNT and beta-catenin signalling: diseases and therapies.
2004,
Pubmed
Moon,
From cortical rotation to organizer gene expression: toward a molecular explanation of axis specification in Xenopus.
1998,
Pubmed
,
Xenbase
Moravec,
[Colorectal cancer and canonical Wnt signalling pathway].
2012,
Pubmed
Morin,
Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC.
1997,
Pubmed
Ng,
Antioxidative activity of natural products from plants.
2000,
Pubmed
Panossian,
Inhibition of arachidonic acid 5-lipoxygenase of human polymorphonuclear leukocytes by esculetin.
1984,
Pubmed
Peifer,
Wnt signaling in oncogenesis and embryogenesis--a look outside the nucleus.
2000,
Pubmed
Polakis,
Wnt signaling and cancer.
2000,
Pubmed
Poy,
Structure of a human Tcf4-beta-catenin complex.
2001,
Pubmed
,
Xenbase
Segditsas,
Colorectal cancer and genetic alterations in the Wnt pathway.
2006,
Pubmed
Sekiya,
Selective inhibition of platelet lipoxygenase by esculetin.
1982,
Pubmed
Shtutman,
The cyclin D1 gene is a target of the beta-catenin/LEF-1 pathway.
1999,
Pubmed
Sokol,
Wnt signaling and dorso-ventral axis specification in vertebrates.
1999,
Pubmed
Sommer,
San1p, checking up on nuclear proteins.
2005,
Pubmed
Tetsu,
Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells.
1999,
Pubmed
Wang,
Wnt signaling in mammalian development: lessons from mouse genetics.
2012,
Pubmed
Wodarz,
Mechanisms of Wnt signaling in development.
1998,
Pubmed
,
Xenbase
Yang,
Aesculetin-induced apoptosis through a ROS-mediated mitochondrial dysfunction pathway in human cervical cancer cells.
2010,
Pubmed
