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

• Published in: Toxicology reports 2020-01, Vol.7, p.1564-1570
• Main Authors: Kwok, Man Long, Li, Zhen Ping, Law, Tin Yu Samuel, Chan, King Ming
• Format: Article
• Language: English
• Subjects: Cadmium toxicity; Cadmium uptake; Copper transporter; Regular; Stable cell line
• ISSN: 2214-7500; 2214-7500
• DOI: 10.1016/j.toxrep.2020.11.005

[Display omitted] •CTR1-overexpressing HepG2 and ZFL cell lines were created.•CTR1 overexpression in both HepG2 and ZFL cells increased Cd2+ uptake and toxicity.•CTR1 knockdown in HepG2 cells decreased Cd2+ uptake and toxicity.•CTR1 plays a significant role in Cd2+ uptake and toxicity. Cadmium (Cd2+) is considered a human carcinogen as it causes oxidative stress and alters DNA repair responses. However, how Cd2+ is taken up by cells remains unclear. We hypothesized that Cd2+ could be transported into cells via a membrane copper (Cu) transporter, CTR1. CTR1 expression was not affected by Cd2+ 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 Cd2+ insult. It was found that both HepG2 and ZFL cells overexpressing CTR1 had higher Cd2+ uptake and thus became sensitive to Cd2+. In contrast, hCTR1 knockdown in HepG2 cells led to a reduced uptake of Cd2+, making the cells relatively resistant to Cd2+. Localization studies revealed that hCTR1 had a clustered pattern after Cd2+ exposure, possibly in an attempt to reduce both Cd2+ uptake and Cd2+-induced toxicity. These in vitro results indicate that CTR1 can transport Cd2+ into the cell, resulting in Cd2+ toxicity.