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JNK/AP-1 pathway is involved in tumor necrosis factor-alpha induced expression of vascular endothelial growth factor in MCF7 cells

  1. Author:
    Yin, Y. M.
    Wang, S.
    Sun, Y. J.
    Matt, Y.
    Colburn, N. H.
    Shu, Y. Q.
    Han, X.

  2. Author Address

    Yin, Yongmei, Shu, Yongqian] Nanjing Med Univ, Affiliated Hosp 1, Dept Oncol, Nanjing 210029, Peoples R China. [Sun, Yujie, Han, Xiao] Nanjing Med Univ, Key Lab Human Funct Genom Jiangsu Prov, Nanjing 210029, Peoples R China. [Matt, Young, Colburn, Nancy H.] Ctr Canc Res, Lab Cancer Prevent, Natl Canc Inst, Frederick, MD 21702 USA. [Wang, Shui] Nanjing Med Univ, Affiliated Hosp 1, Dept Gen Surg, Nanjing 210029, Peoples R China.
    1. Year: 2009
  2. Journal: Biomedicine and Pharmacotherapy
    1. 63
    2. 6
    3. Pages: 429-435
  4. Type of Article: Article
  1. Abstract:

    Vascular endothelial growth factor (VEGF) has been implicated in breast tumor angiogenesis. And tumor necrosis factor-alpha (TNF-alpha) is a positive regulator of VEGF. This study was aimed to identify the signalling pathway of TNF-alpha in VEGF expression regulation in breast cancer cell line MCF7. Using luciferase reporter assays, we demonstrated that TNF-alpha significantly increased activator protein-1 (AP-1) transcriptional activity in the MCF7 cells. The expression of the AP-1 family members c-Jun, c-Fos and JunB and phosphorylation levels of c-Jun were upregulated by TNF-alpha, whereas other AP-1 family members Fra-1, Fra-2, and JunD were unaffected. The activation of AP-1 was associated with the formation of p-c-Jun-c-Jun and p-c-Jun-JunB homodimers. Furthermore, the phosphorylation levels of c-Jun N-terminal kinase (JNK) but not P38 and ERK were elevated by TNF-alpha in MCF7 cells. TNF-alpha potently upregulated the mRNA and protein levels of VEGF, which were significantly reversed by JNK inhibitor SP600125. Finally using chromatin immunoprecipitation (CHIP) assays, we found that p-c-Jun bound to the VEGF promoter and regulated VEGF transcription directly. These data suggest that the pro-inflammatory cytokine TNF-alpha is a critical regulator of VEGF expression in breast cancer cells, at least partially via a JNK and AP-1 dependent pathway. (C) 2009 Elsevier Masson SAS. All rights reserved.

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  2. DOI: 10.1016/j.biopha.2009.04.045
  3. PMID: 19553068

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