Bufalin inhibits migration and invasion in human hepatocellular carcinoma SK-Hep1 cells through the inhibitions of NF-kB and matrix metalloproteinase-2/-9-signaling pathways

Authors

  • Ya-Yin Chen,

    1. Department of Chinese-Western Medicine Integration, Chung Shan Medical University Hospital, Taichung, Taiwan, ROC
    2. School of Medicine, Chung Shan Medical University, Taichung, Taiwan, ROC
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    • *The authors, Ya-Yin Chen, Hsu-Feng Lu, Jing-Gung Chung, and Jin-Biou Chang contributed equally to this work.

  • Hsu-Feng Lu,

    1. Department of Clinical Pathology, Cheng Hsin General Hospital, Taipei, Taiwan, ROC
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    • *The authors, Ya-Yin Chen, Hsu-Feng Lu, Jing-Gung Chung, and Jin-Biou Chang contributed equally to this work.

  • Shu-Chun Hsu,

    1. Department of Nutrition, China Medical University, Taichung, Taiwan, ROC
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  • Chao-Lin Kuo,

    1. School of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, China Medical University, Taichung, Taiwan, ROC
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  • Shu-Jen Chang,

    1. School of Pharmacy, China Medical University, Taichung, Taiwan, ROC
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  • Jen-Jyh Lin,

    1. Graduate Institute of Chinese Medicine, China Medical University, Taichung, Taiwan, ROC
    2. Division of Cardiology, China Medical University Hospital, Taichung, Taiwan, ROC
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  • Ping-Ping Wu,

    1. School of Pharmacy, China Medical University, Taichung, Taiwan, ROC
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  • Jia-You Liu,

    1. Department of Clinical Pathology, Cheng Hsin General Hospital, Taipei, Taiwan, ROC
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  • Ching-Hsiao Lee,

    1. Jen-The Junior College of Medicine, Nursing and Management, Miaoli County, Taiwan, ROC
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  • Jing-Gung Chung,

    Corresponding author
    1. Department of Biological Science and Technology, China Medical University, Taichung, Taiwan, ROC
    2. Department of Microbiology, School of Medicine, China Medical University, Taichung, Taiwan, ROC
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    • *The authors, Ya-Yin Chen, Hsu-Feng Lu, Jing-Gung Chung, and Jin-Biou Chang contributed equally to this work.

  • Jin-Biou Chang

    Corresponding author
    1. Department of Pathology, National Defense Medical Center, Division of Clinical Pathology, Tri-Service General Hospital, Taipei, Taiwan, ROC
    2. Department of Medical Laboratory Science and Biotechnology, Yuanpei University, Hsinchu, Taiwan, ROC
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    • *The authors, Ya-Yin Chen, Hsu-Feng Lu, Jing-Gung Chung, and Jin-Biou Chang contributed equally to this work.


ABSTRACT

Metastasis plays an important role in mortality of cancer patients. Migration and invasion are the major characteristics of tumor metastasis. The induction of matrix metalloproteinases (MMPs) such as MMP-2 and -9 are particularly important for the invasiveness of various cancer cells. Bufalin, a class of toxic steroids, was purified from the skin glands of Bufo gargarizans or Bufo melanostictus; it is known to inhibit proliferation of human cancer cells. In this study, we investigated the antiinvasive mechanisms of bufalin in the human hepatocellular cancer cell line SK-Hep1. Bufalin significantly reduced serum-induced cell invasion and migration. Furthermore, bufalin markedly inhibited MMP-2 and -9 activity, mRNA expression and protein levels in SK-Hep1 cells. Bufalin attenuated phosphoinisitide-3-kinase (PI3K) and phosphorylation of AKT which was associated with reduced levels of nuclear factor kappa B (NF-κB). Bufalin also suppressed protein levels of FAK and Rho A, VEGF, MEKK3, MKK7, and uPA and it diminished NF-κB translocation. Based on these observations, we propose that bufalin is acts as an antiinvasive agent by inhibiting MMP-2 and -9 and involving PI3K/AKT and NF-κB pathways. Bufalin is a potential therapeutic agent that may have efficacy in preventing the invasion and metastasis of malignant liver tumors. © 2013 Wiley Periodicals, Inc. Environ Toxicol 30: 74–82, 2015.

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