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Regulation of copper ion transporter expression by copper and silver in A549 cells

Silver nanoparticles are widely used in various medical applications and are currently under investigation as potential chemotherapeutic agents. Sensitivity to silver as a chemotherapeutic agent may be associated with transport of silver cations (Ag+) through copper ion transporters. Consequently, we investigated the effect of copper and silver on copper ion transporters in A549 cells, a human alveolar epithelial carcinoma cell line. In human cells, there are two copper importers (Ctr1 and Ctr2) and two copper exporters (ATP7A & ATP7B). Using an MTT assay, silver ions showed a cytotoxic effect on A549 cells in a dose dependent fashion within range of 2–50 mg/ml Ag‐acetate with a lethal dose 50% (LD50) of ~20 mg/ml. In contrast, exposure to cuprous chloride (CuCl) was not cytotoxic at a concentration of 100 mg/ml. Using RT‐PCR, we discovered that (1) Ctr1 mRNA is expressed in A549 cells and expression is increased with Cu+, but not with Ag+, (2) Ctr2 mRNA is not detected in control or Ag+‐treated cells, but is induced by Cu+, (3) ATP7A mRNA was not affected either by Cu+ or Ag+ ions and (4) ATP7B mRNA was neither detected in control nor induced by Cu+ or Ag+ ions. Protein expression of CTR1 and CTR2 assayed by Western blot corroborated the RT‐PCR results. We conclude that exposure to copper increases the transcription of copper ion transporters in A549 cells. Silver may have similar effects, but of a lesser magnitude.