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.

Original languageEnglish
Pages (from-to)315-322
Number of pages8
JournalEnvironmental Toxicology
Volume30
Issue number3
DOIs
Publication statusPublished - Mar 1 2015

Keywords

  • AP-1
  • Carcinogenesis
  • ERK1/2
  • IL-8
  • MAPK
  • Pb

ASJC Scopus subject areas

  • Health, Toxicology and Mutagenesis
  • Toxicology
  • Management, Monitoring, Policy and Law
  • Medicine(all)

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