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Esculetin suppresses proliferation of human colon cancer cells by directly targeting ?-catenin.

ABSTRACT: The Wnt pathway is a promising therapeutic and preventive target in various human cancers. The transcriptional complex of ?-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 ?-catenin-TcF complex to suppress cancer cell growth with fewer adverse side effects is needed. To identify compounds that inhibit the association between ?-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-?-catenin pathway. We then evaluated the effect of esculetin on the growth of various human colon cancer cell lines and its effect on Wnt-?-catenin signaling in cells and in an embryonic model. Esculetin disrupted the formation of the ?-catenin-Tcf complex through direct binding with the Lys312, Gly307, Lys345, and Asn387 residues of ?-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 ?-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 ?-catenin inhibits the formation of the ?-catenin-Tcf complex, which could contribute to esculetin's positive therapeutic and preventive effects against colon carcinogenesis.

SUBMITTER: Lee SY

PROVIDER: S-EPMC3885338 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Esculetin suppresses proliferation of human colon cancer cells by directly targeting β-catenin.

Lee Sung-Young SY Lim Tae-Gyu TG Chen Hanyong H Jung Sung Keun SK Lee Hyo-Jeong HJ Lee Mee-Hyun MH Kim Dong Joon DJ Shin Aram A Lee Ki Won KW Bode Ann M AM Surh Young-Joon YJ Dong Zigang Z

Cancer prevention research (Philadelphia, Pa.) 20131008 12

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 effe ...[more]

PMID: 24104353

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Project description:BACKGROUND:A handful of studies have exploited antitumor potential of esculetin, a dihydroxy coumarine derivative; the targets to which it binds and the possible downstream mechanism for its cytotoxicity in cancer cells remain to be elucidated. Using pancreatic cancer cell lines as a model system, herein the study was initiated to check the efficacy of esculetin in inhibiting growth of these cancer cells, to decipher mechanism of its action and to predict its direct binding target protein. METHODS:The cytotoxicity of esculetin was determined in PANC-1, MIA PaCa-2 and AsPC-1 cell lines; followed by an inspection of intracellular levels of ROS and its associated transcription factor, p65-NF-?B. The interaction between transcription factor, Nrf2 and its regulator KEAP1 was studied in the presence and absence of esculetin. The effect of Nrf2 on gene expression of antioxidant response element pathway was monitored by real time PCR. Thereafter, potential binding target of esculetin was predicted through molecular docking and then confirmed in vitro. RESULTS:Esculetin treatment in all three pancreatic cancer cell lines resulted in significant growth inhibition with G1-phase cell cycle arrest and induction of mitochondrial dependent apoptosis through activation of caspases 3, 8 and 9. A notable decrease was observed in intracellular ROS and protein levels of p65-NF-?B in PANC-1 cells on esculetin treatment. Antioxidant response regulator Nrf2 has been reportedly involved in crosstalk with NF-?B. Interaction between Nrf2 and KEAP1 was found to be lost upon esculetin treatment in PANC-1 and MIA Paca-2 cells. Nuclear accumulation of Nrf2 and an upregulation of expression of Nrf2 regulated gene NQO1, observed on esculetin treatment in PANC-1 further supported the activation of Nrf2. To account for the loss of Nrf2-KEAP1 interaction on esculetin treatment, direct binding potential between esculetin and KEAP1 was depicted in silico using molecular docking studies. Pull down assay using esculetin conjugated sepharose beads confirmed the binding between esculetin and KEAP1. CONCLUSIONS:We propose that esculetin binds to KEAP1 and inhibits its interaction with Nrf2 in pancreatic cancer cells. This thereby promotes nuclear accumulation of Nrf2 in PANC-1 cells that induces antiproliferative and apoptotic response possibly by attenuating NF-?B.

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Esculetin suppresses proliferation of human colon cancer cells by directly targeting ?-catenin.

Publications

Esculetin suppresses proliferation of human colon cancer cells by directly targeting β-catenin.

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