Aberrant cytokine secretion and zinc uptake in chronic cadmium-exposed lung epithelial cells

Proteomics Clin Appl. 2017 Mar;11(3-4). doi: 10.1002/prca.201600059. Epub 2016 Dec 14.


Purpose: Our previous results showed that cadmium (Cd)-adapted lung epithelial cells (LECs) developed resistance to apoptosis due to non-responsiveness of the c-Jun N-terminal kinase pathway and augmented expression of cytokeratin 8. Since cellular Cd entry is a prerequisite in order for Cd to elicit its cytotoxicity, therefore, we wonder if there are differential metal ion transport ability and also other phenotypic changes that occurred in these Cd-resistant LECs.

Experimental design and results: Here, we explored further and found that the zinc (Zn) importer Zip8 was stably abolished in these cells along with a marked decrease of Cd and Zn accumulation. Moreover, by cell migration assays and cytokine antibody array analysis, we found that Cd-adapted cells exhibit enhanced migratory ability possibly due to elevated secretions of vascular endothelial growth factor and macrophage inflammatory protein-3 alpha (MIP-3α).

Conclusion and clinical relevance: Taken together, our results show that during chronic Cd exposure, lung cells antagonize excessive cellular Cd-influx by abolishing Zip8 expression to reduce Cd-toxicity; however, this also renders cells with a diminished Zn uptake. The imbalance of Zn homeostasis and elevation of angiogenic and epithelial-mesenchymal transition-promoting cytokines in Cd-adapted cells might thus likely promote Zn deficiency, angiogenesis, and cell invasion.

Keywords: Biomarker; Cadmium; MIP-3α; VEGF; Zip8.

MeSH terms

  • Adaptation, Physiological / drug effects
  • Antibodies, Neutralizing / immunology
  • Biological Transport / drug effects
  • Biomarkers / metabolism
  • Cadmium / toxicity*
  • Cation Transport Proteins / metabolism
  • Cell Movement / drug effects
  • Chemokine CCL20 / immunology
  • Cytokines / metabolism*
  • Epithelial Cells / cytology
  • Epithelial Cells / drug effects*
  • Epithelial Cells / metabolism*
  • Humans
  • Lung / cytology*
  • Time Factors
  • Vascular Endothelial Growth Factor A / immunology
  • Zinc / metabolism*


  • Antibodies, Neutralizing
  • Biomarkers
  • CCL20 protein, human
  • Cation Transport Proteins
  • Chemokine CCL20
  • Cytokines
  • SLC39A8 protein, human
  • Vascular Endothelial Growth Factor A
  • Cadmium
  • Zinc