Esculetin Suppresses Proliferation of Human Colon Cancer Cells by Directly Targeting β-Catenin

Abstract

The Wnt pathway is a promising therapeutic and preventive target in various human cancers. The transcriptional complex of β-catenin/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. Aesculetin, 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 aesculetin 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. Aesculetin 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. Additionally, aesculetin effectively decreased viability and inhibited anchorage-independent growth of colon cancer cells. Aesculetin potently antagonized the cellular effects of β-catenin-dependent activity and in vivo treatment with aesculetin suppressed tumor growth in a colon cancer xenograft mouse model. Our data indicate that the interaction between aesculetin and β-catenin inhibits the formation of the β-catenin/Tcf complex, which could contribute to aesculetin’s positive therapeutic and preventive effects against colon carcinogenesis.

Structure–activity relationship studies of 4-methylcoumarin derivatives as anticancer agents

“…Natural coumarins, such as osthole (Zhang et al, 2012), esculetin (Lee et al, 2013), and umbelliferone (Weber et al, 1998) as well as several coumarin containing plant extracts, have been reported to inhibit the growth of cancer cells (Li et al, 2013;Ngo et al, 2010).…”

Mass Spectrometry in Clinical Diagnosis: A Preliminary Application in Tumor Cellular Proteomics for Biomarker Discovery

“…Colorectal cancer symptoms include a change in bowel habits or bleeding, but often there are no symptoms. Most colorectal cancers originate from small, noncancerous (benign) tumors called adenomatous polyps that form on the inner walls of the large intestine [13][14][15][16].…”

An insight into the role of citrus bioactives in modulation of colon cancer

“…A decrease in tumour growth has been reported with esculetin in colon cancer xenograft mouse model. Further, computer docking studies indicated that esculetin disrupted the formation of β-catenin-T cell factor complexes of Wnt signalling pathway (a major pathway in progression of colon cancer) by directly binding to the amino acid residues of β-catenin, thus offering itself as a potent antagonistic agent against β-catenin mediated colon cancer (Lee et al, 2013b).…”