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Research ArticleCELLULAR AND MOLECULAR

Mammalian Target of Rapamycin Pathway Promotes Tumor-Induced Angiogenesis in Adenoid Cystic Carcinoma: Its Suppression by Isoliquiritigenin through Dual Activation of c-Jun NH2-Terminal Kinase and Inhibition of Extracellular Signal-Regulated Kinase

Zhi-Jun Sun, Gang Chen, Wei Zhang, Xiang Hu, Cong-Fa Huang, Yu-Fan Wang, Jun Jia and Yi-Fang Zhao
Journal of Pharmacology and Experimental Therapeutics August 2010, 334 (2) 500-512; DOI: https://doi.org/10.1124/jpet.110.167692
Zhi-Jun Sun
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Gang Chen
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Wei Zhang
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Xiang Hu
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Cong-Fa Huang
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Yu-Fan Wang
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Jun Jia
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Yi-Fang Zhao
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Abstract

Tumor-induced angiogenesis is essential for invasive growth and hematogenous metastasis of adenoid cystic carcinoma (ACC), a highly aggressive neoplasm mostly occurring in salivary glands. Previous studies have indicated that strategies directed against angiogenesis will help develop new therapeutic agents for ACC. The Chinese folk medicine licorice has been used for years as a natural remedy for angiogenesis-related diseases. In this study, we examined the effects of isoliquiritigenin (ISL), a flavonoid isolated from licorice, on the growth and viability of ACC cells and observed a concentration-dependent (0–20 μM) inhibition of cell growth without cell death at 24 h. In a further mimic coculture study, ISL effectively suppressed the ability of ACC cells to induce in vitro proliferation, migration, and tube formation of human endothelial hybridoma (EAhy926) cells as well as ex vivo and in vivo angiogenesis, whereas it exerted no effect on EAhy926 cells when added directly or in the presence of vascular endothelial growth factor (VEGF). The data also showed that the specific suppression of tumor angiogenesis by ISL was caused by down-regulation of mammalian target of rapamycin (mTOR) pathway-dependent VEGF production by ACC cells, correlating with concurrent activation of c-Jun NH2-terminal kinase (JNK) and inhibition of extracellular signal-regulated kinase (ERK). Most importantly, ISL also significantly decreased microvessel density within xenograft tumors, associating with the reduction of VEGF production and suppression of the mTOR pathway coregulated by JNK and ERK, as revealed by immunohistochemical studies and clustering analysis. Taken together, our results highlight the fact that ISL is a novel inhibitor of tumor angiogenesis and possesses great therapeutic potential for ACC.

Footnotes

  • This study was supported in part by the National Natural Science Foundation of China [Grants 30872894, 30973330, 30801305] (to Y.F.Z. and J.J.); and the National Undergraduate Innovative Experiment Project [Grant 091048654] (to G.C.).

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

    doi:10.1124/jpet.110.167692.

  • ABBREVIATIONS:

    ACC
    adenoid cystic carcinoma
    ISL
    isoliquiritigenin
    VEGF
    vascular endothelial growth factor
    mTOR
    mammalian target of rapamycin
    ERK
    extracellular signal-regulated kinase
    MAPK
    mitogen-activated protein kinase
    JNK
    c-Jun NH2-terminal kinase
    NSG
    normal salivary gland
    TSC
    tuberous sclerosis complex
    NF-κB
    nuclear factor-κB
    PBS
    phosphate-buffered saline
    p
    phospho
    MVD
    microvessel density
    DMEM
    Dulbecco's modified Eagle's medium
    FBS
    fetal bovine serum
    CM
    conditioned medium
    CAM
    chick chorioallantoic membrane
    RT
    reverse transcription
    PCR
    polymerase chain reaction
    bFGF
    basic fibroblast growth factor
    G-CSF
    granulocyte colony-stimulating factor
    PDGF
    platelet-derived growth factor
    ELISA
    enzyme-linked immunosorbent assay
    PI3K
    phosphatidylinositol 3-kinase
    IKK
    IκBα kinase
    GSK
    glycogen synthetase kinase
    SP600125
    anthra(1,9-cd)pyrazol-6(2H)-one-1,9-pyrazoloanthrone
    PD98059
    2′-amino-3′-methoxyflavone.

  • Received March 11, 2010.
  • Accepted May 17, 2010.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 368 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 368, Issue 3
1 Mar 2019
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Mammalian Target of Rapamycin Pathway Promotes Tumor-Induced Angiogenesis in Adenoid Cystic Carcinoma: Its Suppression by Isoliquiritigenin through Dual Activation of c-Jun NH2-Terminal Kinase and Inhibition of Extracellular Signal-Regulated Kinase
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Research ArticleCELLULAR AND MOLECULAR

Mammalian Target of Rapamycin Pathway Promotes Tumor-Induced Angiogenesis in Adenoid Cystic Carcinoma: Its Suppression by Isoliquiritigenin through Dual Activation of c-Jun NH2-Terminal Kinase and Inhibition of Extracellular Signal-Regulated Kinase

Zhi-Jun Sun, Gang Chen, Wei Zhang, Xiang Hu, Cong-Fa Huang, Yu-Fan Wang, Jun Jia and Yi-Fang Zhao
Journal of Pharmacology and Experimental Therapeutics August 1, 2010, 334 (2) 500-512; DOI: https://doi.org/10.1124/jpet.110.167692

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Research ArticleCELLULAR AND MOLECULAR

Mammalian Target of Rapamycin Pathway Promotes Tumor-Induced Angiogenesis in Adenoid Cystic Carcinoma: Its Suppression by Isoliquiritigenin through Dual Activation of c-Jun NH2-Terminal Kinase and Inhibition of Extracellular Signal-Regulated Kinase

Zhi-Jun Sun, Gang Chen, Wei Zhang, Xiang Hu, Cong-Fa Huang, Yu-Fan Wang, Jun Jia and Yi-Fang Zhao
Journal of Pharmacology and Experimental Therapeutics August 1, 2010, 334 (2) 500-512; DOI: https://doi.org/10.1124/jpet.110.167692
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