Pb2+ induced IL-8 gene expression by extracellular signal-regulated kinases and the transcription factor, activator protein 1, in human gastric carcinoma cells

Authors

  • Ying-Chi Lin,

    1. School of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan
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    • These authors contributed equally to this work.

  • Po-Li Wei,

    1. Department of Surgery, College of Medicine, Taipei Medical University, Taiwan
    2. Division of General Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan
    3. Cancer Center, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan
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    • These authors contributed equally to this work.

  • Yao-Ting Tsai,

    1. Department of Medical Genetics, Kaohsiung Medical University, Taiwan
    2. Department of Clinical Pharmacy, School of Pharmacy, Taipei Medical University, Taipei, Taiwan
    3. Master Program for Clinical Pharmacogenomics and Pharmacoproteomics, School of Pharmacy, Taipei Medical University, Taipei, Taiwan
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    • These authors contributed equally to this work.

  • Jhen-Hong Wong,

    1. Department of Medical Genetics, Kaohsiung Medical University, Taiwan
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  • Che-Mai Chang,

    1. Department of Clinical Pharmacy, School of Pharmacy, Taipei Medical University, Taipei, Taiwan
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  • Jaw-Yuan Wang,

    1. Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
    2. Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
    3. Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
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  • Ming-Feng Hou,

    1. Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
    2. Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
    3. Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
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  • Yi-Chao Lee,

    1. Ph.D. Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
    2. Center for Neuro Trauma and Neuro Regeneration, Taipei Medical University, Taipei, Taiwan
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  • Hung-Yi Chuang,

    1. Department of Public Health, Kaohsiung Medical University, Kaohsiung, Taiwan
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  • Wei-Chiao Chang

    Corresponding author
    1. Department of Medical Genetics, Kaohsiung Medical University, Taiwan
    2. Department of Clinical Pharmacy, School of Pharmacy, Taipei Medical University, Taipei, Taiwan
    3. Master Program for Clinical Pharmacogenomics and Pharmacoproteomics, School of Pharmacy, Taipei Medical University, Taipei, Taiwan
    4. Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
    5. Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
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ABSTRACT

Divalent lead (Pb2+) is a common industrial pollutant epidemiologically associated with gastric cancers. Pb2+ was found to promote tumorigenesis, which may include interleukin (IL)-8, a pro-inflammatory chemokine that promotes angiogenesis and tumor metastasis. Given that the gastrointestinal tract is a major route of Pb2+ exposure, we investigated the ability of Pb2+ to induce IL-8 expression in gastric carcinoma cells and its underlying mechanism. At a concentration of 0.1 μM, Pb2+ induced IL-8 gene activation in gastric carcinoma AGS cells. Using a IL-8 promoter-deletion analysis, transcription factor activator protein 1 (AP-1) was identified as a necessary component of Pb2+-induced IL-8 gene activation. Upregulation of the IL-8 gene was abrogated by the MEK inhibitor, PD98059, and partially suppressed by the epidermal growth factor receptor inhibitors, AG1478 and PD153035. Furthermore, c-Jun protein expression was induced in cells treated with Pb2+, and overexpression of c-Jun enhanced Pb2+-induced IL-8 activation. Collectively, our findings highlight the pivotal roles of AP-1 and extracellular signal-regulated kinase in signal transduction of Pb2+-induced IL-8 gene activation. These molecules may be potential therapeutic targets for Pb2+-related inflammation leading to stomach carcinogenesis. © 2013 Wiley Periodicals, Inc. Environ Toxicol 30: 315–322, 2015.

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