Promotion of cadmium uptake and cadmium-induced toxicity by the copper transporter CTR1 in HepG2 and ZFL cells

Cadmium (Cd(2+)) is considered a human carcinogen as it causes oxidative stress and alters DNA repair responses. However, how Cd(2+) is taken up by cells remains unclear. We hypothesized that Cd(2+) could be transported into cells via a membrane copper (Cu) transporter, CTR1. CTR1 expression was not affected by Cd(2+) exposure at the mRNA or protein level. Stable cell lines overexpressing either hCTR1, in the human liver cell line HepG2, or zCTR1, in the zebrafish liver cell line ZFL, were created to study their responses to Cd(2+) insult. It was found that both HepG2 and ZFL cells overexpressing CTR1 had higher Cd(2+) uptake and thus became sensitive to Cd(2+). In contrast, hCTR1 knockdown in HepG2 cells led to a reduced uptake of Cd(2+), making the cells relatively resistant to Cd(2+). Localization studies revealed that hCTR1 had a clustered pattern after Cd(2+) exposure, possibly in an attempt to reduce both Cd(2+) uptake and Cd(2+)-induced toxicity. These in vitro results indicate that CTR1 can transport Cd(2+) into the cell, resulting in Cd(2+) toxicity.