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Regulation of activator protein-1 activity in the mediastinal lymph node metastasis of lung cancer

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Abstract

Orthotopic implantation of a metastatic cell line of Lewis lung carcinoma (LLC-MLN), which was isolated by an in vivo selection method, resulted in greater metastatic growth in mediastinal lymph nodes as compared with that of the original LLC cells. LLC-MLN cells also had increased invasive ability and activator protein-1 (AP-1) transcriptional activity as compared with the original LLC cells. This is well consistent with the previously reported finding that overexpression of AP-1 is associated with lymphatic metastasis in lung cancer patients. Oral administration of curcumin, which downregulates AP-1 transcription, significantly inhibited the mediastinal lymph node metastasis of orthotopically implanted LLC cells in a dose-dependent manner, but did not affect the tumor growth at the implantation site. Combined treatment with curcumin and an anti-cancer drug, cis-diamine-dichloroplatinum (CDDP), resulted in a marked inhibition of tumor growth at the implanted site and of lymphatic metastasis, and a significant prolongation of the survival time. The downregulation of transcriptional AP-1 activity by curcumin as seen in the dual luciferase assay caused inhibition of LLC cell invasion through the repression of expression of the mRNAs for urokinase-type plasminogen activator (u-PA) and its receptor (u-PAR). Inhibition of AP-1 transcriptional activity may offer improved therapeutic efficacy for lung cancer patients with lymphatic metastasis.

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Authors and Affiliations

  1. Department of Pathogenic Biochemistry, Institute of Natural Medicine, Japan

    Katsuyuki Ichiki, Noriyasu Mitani & Ikuo Saiki

  2. First Department of Surgery, Toyama Medical and Pharmaceutical University, Sugitani, Toyama, Japan

    Yoshinori Doki, Hiroiku Hara & Takuro Misaki

Authors
  1. Katsuyuki Ichiki
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  2. Noriyasu Mitani
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  3. Yoshinori Doki
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  4. Hiroiku Hara
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  5. Takuro Misaki
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  6. Ikuo Saiki
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Ichiki, K., Mitani, N., Doki, Y. et al. Regulation of activator protein-1 activity in the mediastinal lymph node metastasis of lung cancer. Clin Exp Metastasis 18, 539–545 (2000). https://doi.org/10.1023/A:1011980313237

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