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Molecular Pharmacology

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Research ArticleArticle

A Superoxide-Mediated Mitogen-Activated Protein Kinase Phosphatase-1 Degradation and c-Jun NH2-Terminal Kinase Activation Pathway for Luteolin-Induced Lung Cancer Cytotoxicity

Lang Bai, Xiuling Xu, Qiong Wang, Shanling Xu, Wei Ju, Xia Wang, Wenshu Chen, Weiyang He, Hong Tang and Yong Lin
Molecular Pharmacology April 2012, 81 (4) 549-555; DOI: https://doi.org/10.1124/mol.111.076653
Lang Bai
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Xiuling Xu
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Qiong Wang
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Shanling Xu
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Wei Ju
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Xia Wang
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Wenshu Chen
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Weiyang He
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Hong Tang
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Yong Lin
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Abstract

Although luteolin is identified as a potential cancer therapeutic and preventive agent because of its potent cancer cell-killing activity, the molecular mechanisms by which its cancer cell cytotoxicity is achieved have not been well elucidated. In this report, luteolin-induced cellular signaling was systematically investigated, and a novel pathway for luteolin's lung cancer killing was identified. The results show that induction of superoxide is an early and crucial step for luteolin-induced apoptotic and nonapoptotic death in lung cancer cells. The c-Jun N-terminal kinase (JNK) was potently activated after superoxide accumulation. Suppression of superoxide completely blocked luteolin-induced JNK activation, which was well correlated to alleviation of luteolin's cytotoxicity. Although luteolin slightly stimulated the JNK-activating kinase mitogen-activated protein kinase kinase 7, the latter was not dependent on superoxide. We further found that luteolin triggers a superoxide-dependent rapid degradation of the JNK-inactivating phosphatase mitogen-activated protein kinase phosphatase-1 (MKP-1). Introduction of a degradation-resistant MKP-1 mutant effectively attenuated luteolin-induced JNK activation and cytotoxicity, suggesting that inhibition of the JNK suppressor MKP-1 plays a major role in luteolin-induced lung cancer cell death. Taken together, our results unveil a novel pathway consisting of superoxide, MKP-1, and JNK for luteolin's cytotoxicity in lung cancer cells, and manipulation of this pathway could be a useful approach for applying luteolin for lung cancer prevention and therapy.

Footnotes

  • This work was supported in part by the National Institutes of Health National Cancer Institute [Grant R03-CA125796] and Department of Energy Low Dose Radiation Research Program [Grant DE-SC0001173].

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

    http://dx.doi.org/10.1124/mol.111.076653.

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

  • ABBREVIATIONS:

    ROS
    reactive oxygen species
    TNF
    tumor necrosis factor
    NF-κB
    nuclear factor κB
    JNK
    c-Jun N-terminal kinase
    MKP-1
    mitogen-activated protein kinase phosphatase
    BHA
    butylated hydroxyanisol
    z-VAD
    N-benzyloxycarbonyl-Val-Ala-Asp(O-Met)
    NAC
    N-acetylcysteine
    SP600125
    1,9-pyrazoloanthrone
    SB203580
    4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole
    ERK
    extracellular signal-regulated kinase
    U0126
    1,4-diamino-2,3-dicyano-1,4-bis(methylthio)butadiene
    IKK
    IκB kinase complex
    Ro 31-9549
    2-[1-3-(aminopropyl)indol-3-yl]-3-(1-methyl-1H-indol-3-yl) maleimide
    Gö6976
    12-(2-cyanoethyl)-6,7,12,13-tetrahydro-13-methyl-5-oxo-5H-indolo(2,3-a)pyrrolo(3,4-c)-carbazole
    MG132
    N-benzoyloxycarbonyl (Z)-Leu-Leu-leucinal
    MKK
    mitogen-activated protein kinase kinase
    DHE
    dihydroethidium
    PCR
    polymerase chain reaction
    MAPKKK
    mitogen-activated protein kinase kinase kinase
    MAPKK
    mitogen-activated protein kinase kinase
    CHX
    cycloheximide.

  • Received November 2, 2011.
  • Accepted January 5, 2012.
  • Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 81 (4)
Molecular Pharmacology
Vol. 81, Issue 4
1 Apr 2012
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Research ArticleArticle

MKP-1 in Anticancer Activity of Luteolin

Lang Bai, Xiuling Xu, Qiong Wang, Shanling Xu, Wei Ju, Xia Wang, Wenshu Chen, Weiyang He, Hong Tang and Yong Lin
Molecular Pharmacology April 1, 2012, 81 (4) 549-555; DOI: https://doi.org/10.1124/mol.111.076653

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Research ArticleArticle

MKP-1 in Anticancer Activity of Luteolin

Lang Bai, Xiuling Xu, Qiong Wang, Shanling Xu, Wei Ju, Xia Wang, Wenshu Chen, Weiyang He, Hong Tang and Yong Lin
Molecular Pharmacology April 1, 2012, 81 (4) 549-555; DOI: https://doi.org/10.1124/mol.111.076653
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