Raf and PI3K are the Molecular Targets for the Anti-metastatic Effect of Luteolin

Authors

  • Ho Young Kim,

    1. WCU Major in Biomodulation, Department of Agricultural Biotechnology, Seoul National University, Seoul, Republic of Korea
    2. Department of Agricultural Biotechnology, Seoul National University, Seoul, 151-921, Republic of Korea
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    • Ho Young Kim and Sung Keun Jung contributed equally to this work.
  • Sung Keun Jung,

    1. WCU Major in Biomodulation, Department of Agricultural Biotechnology, Seoul National University, Seoul, Republic of Korea
    2. Department of Agricultural Biotechnology, Seoul National University, Seoul, 151-921, Republic of Korea
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    • Ho Young Kim and Sung Keun Jung contributed equally to this work.
  • Sanguine Byun,

    1. WCU Major in Biomodulation, Department of Agricultural Biotechnology, Seoul National University, Seoul, Republic of Korea
    2. Department of Agricultural Biotechnology, Seoul National University, Seoul, 151-921, Republic of Korea
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  • Joe Eun Son,

    1. Department of Agricultural Biotechnology, Seoul National University, Seoul, 151-921, Republic of Korea
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  • Mi Hyun Oh,

    1. Department of Agricultural Biotechnology, Seoul National University, Seoul, 151-921, Republic of Korea
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  • Jihoon Lee,

    1. WCU Major in Biomodulation, Department of Agricultural Biotechnology, Seoul National University, Seoul, Republic of Korea
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  • Min Jeong Kang,

    1. WCU Major in Biomodulation, Department of Agricultural Biotechnology, Seoul National University, Seoul, Republic of Korea
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  • Yong-Seok Heo,

    1. Department of Chemistry, Konkuk University, Seoul, Republic of Korea
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  • Ki Won Lee,

    Corresponding author
    1. WCU Major in Biomodulation, Department of Agricultural Biotechnology, Seoul National University, Seoul, Republic of Korea
    2. Advanced Institutes of Convergence Technology, Seoul National University, Suwon, Gyeonggi-do, Republic of Korea
    • Department of Agricultural Biotechnology, Seoul National University, Seoul, 151-921, Republic of Korea
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  • Hyong Joo Lee

    Corresponding author
    1. Department of Agricultural Biotechnology, Seoul National University, Seoul, 151-921, Republic of Korea
    2. Advanced Institutes of Convergence Technology, Seoul National University, Suwon, Gyeonggi-do, Republic of Korea
    • WCU Major in Biomodulation, Department of Agricultural Biotechnology, Seoul National University, Seoul, Republic of Korea
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Correspondence to: Hyong Joo Lee, Ph.D.; WCU Biomodulation Major, Department of Agricultural Biotechnology, Seoul National University, Seoul 151-921, Republic of Korea; Ki Won Lee, Ph.D.; Department of Agricultural Biotechnology, Seoul National University, Seoul 151-921, Republic of Korea.

E-mail: leehyjo@snu.ac.kr; kiwon@snu.ac.kr

Abstract

Metastases are the primary cause of human cancer deaths. Luteolin, a naturally occurring phytochemical, has chemopreventive and/or anticancer properties in several cancer cell lines. However, anti-metastatic effects of luteolin in vivo and the underlying molecular mechanisms and target(s) remain unknown. Luteolin suppresses matrix metalloproteinase (MMP)-2 and -9 activities and invasion in murine colorectal cancer CT-26 cells. Western blot and kinase assay data revealed that luteolin inhibited Raf and phosphatidylinositol 3-kinase (PI3K) activities and subsequently attenuated phosphorylation of MEK and Akt. A pull-down assay indicated that luteolin non-competitively bound with ATP to suppress Raf activity and competitively bound with ATP to inhibit PI3K activity. GW5074, a Raf inhibitor, and LY294002, a PI3K inhibitor, inhibited MMP-2 and -9 activities and invasion in CT-26 cells. An in vivo mouse study showed that oral administration (10 or 50 mg/kg) of luteolin significantly inhibited tumor nodules and tumor volume of lung metastasis induced by intravenous injection of CT-26 cells. Luteolin also inhibited MMP-9 expression and activity in CT-26-induced mouse lung tissue. These results suggest that luteolin may have considerable potential for development as an anti-metastatic agent. Copyright © 2012 John Wiley & Sons, Ltd.

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