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Molecular Pharmacology

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Research ArticleArticle

Wnt/β-Catenin Signaling Mediates the Antitumor Activity of Magnolol in Colorectal Cancer Cells

You-Jin Kang, Hyen Joo Park, Hwa-Jin Chung, Hye-Young Min, Eun Jung Park, Min Ai Lee, Yoonho Shin and Sang Kook Lee
Molecular Pharmacology August 2012, 82 (2) 168-177; DOI: https://doi.org/10.1124/mol.112.078535
You-Jin Kang
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Hyen Joo Park
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Hwa-Jin Chung
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Hye-Young Min
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Eun Jung Park
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Min Ai Lee
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Yoonho Shin
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Sang Kook Lee
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Abstract

Abnormal activation of the canonical Wnt/β-catenin pathway and up-regulation of the β-catenin/T-cell factor (TCF) response to transcriptional signaling play a critical role early in colorectal carcinogenesis. Therefore, Wnt/β-catenin signaling is considered an attractive target for cancer chemotherapeutic or chemopreventive agents. Small molecules derived from the natural products were used in our cell-based reporter gene assay to identify potential inhibitors of Wnt/β-catenin signaling. Magnolol, a neolignan from the cortex of Magnolia obovata, was identified as a promising candidate because it effectively inhibited β-catenin/TCF reporter gene (TOPflash) activity. Magnolol also suppressed Wnt3a-induced β-catenin translocation and subsequent target gene expression in human embryonic kidney 293 cells. To further investigate the precise mechanisms of action in the regulation of Wnt/β-catenin signaling by magnolol, we performed Western blot analysis, real-time reverse transcriptase-polymerase chain reactions, and an electrophoretic mobility shift assay in human colon cancer cells with aberrantly activated Wnt/β-catenin signaling. Magnolol inhibited the nuclear translocation of β-catenin and significantly suppressed the binding of β-catenin/TCF complexes onto their specific DNA-binding sites in the nucleus. These events led to the down-regulation of β-catenin/TCF-targeted downstream genes such as c-myc, matrix metalloproteinase-7, and urokinase-type plasminogen activator in SW480 and HCT116 human colon cancer cells. In addition, magnolol inhibited the invasion and motility of tumor cells and exhibited antitumor activity in a xenograft nude mouse model bearing HCT116 cells. These findings suggest that the growth inhibition of magnolol against human colon cancer cells can be partly attributed to the regulation of the Wnt/β-catenin signaling pathway.

Footnotes

  • ↵Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • This work was supported by the Basic Science Research Program through the National Research Foundation of Korea [KRF-2008-313-E00738].

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    http://dx.doi.org/10.1124/mol.112.078535.

  • ABBREVIATIONS:

    GSK3β
    glycogen synthase kinase 3β
    APC
    adenomatous polyposis coli
    Fz
    frizzled
    TCF
    T-cell factor
    MMP
    matrix metalloprotease
    uPA
    urokinase-type plasminogen activator
    HEK
    human embryonic kidney
    hFz1
    human frizzled receptor type 1
    PARP
    poly(ADP-ribose) polymerase
    DMEM
    Dulbecco's modified Eagle's medium
    FBS
    fetal bovine serum
    siRNA
    small interfering RNA
    PCR
    polymerase chain reaction
    CM
    conditioned medium.

  • Received February 27, 2012.
  • Accepted May 1, 2012.
  • Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 82 (2)
Molecular Pharmacology
Vol. 82, Issue 2
1 Aug 2012
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Research ArticleArticle

Magnolol Antitumor Activity through Wnt/β-Catenin Signaling

You-Jin Kang, Hyen Joo Park, Hwa-Jin Chung, Hye-Young Min, Eun Jung Park, Min Ai Lee, Yoonho Shin and Sang Kook Lee
Molecular Pharmacology August 1, 2012, 82 (2) 168-177; DOI: https://doi.org/10.1124/mol.112.078535

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Research ArticleArticle

Magnolol Antitumor Activity through Wnt/β-Catenin Signaling

You-Jin Kang, Hyen Joo Park, Hwa-Jin Chung, Hye-Young Min, Eun Jung Park, Min Ai Lee, Yoonho Shin and Sang Kook Lee
Molecular Pharmacology August 1, 2012, 82 (2) 168-177; DOI: https://doi.org/10.1124/mol.112.078535
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