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Molecular Pharmacology

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Research ArticleArticle

Role of Rad51 Down-Regulation and Extracellular Signal-Regulated Kinases 1 and 2 Inactivation in Emodin and Mitomycin C-Induced Synergistic Cytotoxicity in Human Non–Small-Cell Lung Cancer Cells

Ying-Jhen Su, Min-Shao Tsai, Ya-Hsun Kuo, Yu-Fan Chiu, Chao-Min Cheng, Szu-Ting Lin and Yun-Wei Lin
Molecular Pharmacology April 2010, 77 (4) 633-643; DOI: https://doi.org/10.1124/mol.109.061887
Ying-Jhen Su
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Min-Shao Tsai
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Ya-Hsun Kuo
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Yu-Fan Chiu
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Chao-Min Cheng
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Szu-Ting Lin
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Yun-Wei Lin
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Abstract

Emodin (1,3,8-trihydroxy-6-methyl-anthraquinone) is a natural anthraquinone derivative found in the roots and rhizomes of numerous plants. It is a tyrosine kinase inhibitor and has anticancer effects on lung cancer. Rad51 plays a central role in homologous recombination, and high levels of Rad51 expression are observed in chemo- or radioresistant carcinomas. Our previous studies have shown that the mitogen-activated protein kinase kinase (MKK) 1/2-extracellular signal-regulated kinase (ERK) 1/2 signal pathway maintains the expression of Rad51. Therefore, in this study, we hypothesized that emodin could enhance the effects of the antitumor antibiotic mitomycin C (MMC)-mediated cytotoxicity by decreasing the expression of Rad51 and the phosphorylation of ERK1/2. Exposure of the human non–small-cell lung cancer H1703 or A549 cell lines to emodin decreased the MMC-elicited phosphorylated ERK1/2 and Rad51 levels. Moreover, emodin significantly decreased the MMC-elicited Rad51 mRNA and protein levels by increasing the instability of Rad51 mRNA and protein. In emodin- and MMC-cotreated cells, ERK1/2 phosphorylation was enhanced by constitutively active MKK1/2 (MKK1/2-CA), thus increasing Rad51 protein levels and protein stability. The synergistic cytotoxic effects induced by emodin combined with MMC were remarkably decreased by MKK1-CA-mediated enhancement of ERK1/2 activation. Depletion of endogenous Rad51 expression by small interfering Rad51 RNA transfection significantly enhanced MMC-induced cell death and cell growth inhibition. In contrast, overexpression of Rad51 protects lung cancer cells from the synergistic cytotoxic effects induced by emodin and MMC. We conclude that suppression of Rad51 expression or a combination of emodin with chemotherapeutic agents may be considered as potential therapeutic modalities for lung cancer.

Footnotes

    fn-1
  • This work was supported by the National Science Council of Taiwan [Grant NSC 97-2311-B-415-001-MY3].

  • fn-2
  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.109.061887.

  • fn-3
  • ABBREVIATIONS:

    SCLC
    small cell lung cancer
    NSCLC
    non-small cell lung cancer
    MKK
    mitogen-activated protein kinase kinase
    ERK
    extracellular signal-regulated kinase
    MMC
    mitomycin C
    MMK1/2-CA
    constitutively active mitogen-activated protein kinase kinase 1/2
    HRR
    homologous recombination repair
    CK2
    casein kinase 2
    ALLN
    N-acetyl-Leu-Leu-norleucinal
    DMSO
    dimethyl sulfoxide
    si
    small interfering
    siRNA
    small interfering RNA
    RT-PCR
    reverse transcriptase-polymerase chain reaction
    GAPDH
    glyceraldehyde-3-phosphate dehydrogenase
    MTT
    3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
    CI
    combination index
    U0126
    1,4-diamino-2,3-dicyano-1,4-bis(methylthio)butadiene
    SN-38
    7-ethyl-10-hydroxycamptothecin
    MG132
    N-benzoyloxycarbonyl (Z)-Leu-Leu-leucinal.

    • Received October 23, 2009.
    • Accepted December 30, 2009.
  • Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 77 (4)
Molecular Pharmacology
Vol. 77, Issue 4
1 Apr 2010
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Research ArticleArticle

Role of Rad51 Down-Regulation and Extracellular Signal-Regulated Kinases 1 and 2 Inactivation in Emodin and Mitomycin C-Induced Synergistic Cytotoxicity in Human Non–Small-Cell Lung Cancer Cells

Ying-Jhen Su, Min-Shao Tsai, Ya-Hsun Kuo, Yu-Fan Chiu, Chao-Min Cheng, Szu-Ting Lin and Yun-Wei Lin
Molecular Pharmacology April 1, 2010, 77 (4) 633-643; DOI: https://doi.org/10.1124/mol.109.061887

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Research ArticleArticle

Role of Rad51 Down-Regulation and Extracellular Signal-Regulated Kinases 1 and 2 Inactivation in Emodin and Mitomycin C-Induced Synergistic Cytotoxicity in Human Non–Small-Cell Lung Cancer Cells

Ying-Jhen Su, Min-Shao Tsai, Ya-Hsun Kuo, Yu-Fan Chiu, Chao-Min Cheng, Szu-Ting Lin and Yun-Wei Lin
Molecular Pharmacology April 1, 2010, 77 (4) 633-643; DOI: https://doi.org/10.1124/mol.109.061887
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