Uptake, p53 pathway activation, and cytotoxic responses for Co(II) and Ni(II) in human lung cells: implications for carcinogenicity.
Cobalt(II) and nickel(II) ions display similar chemical properties and act as hypoxia mimics in cells. However, only soluble Co(II) but not soluble Ni(II) is carcinogenic by inhalation. To explore potential reasons for these differences, we examined responses of human lung cells to both metals. We found that Co(II) showed almost 8 times higher accumulation than Ni(II) in H460 cells but caused a less efficient activation of the transcriptional factor p53 as measured by its accumulation, Ser15 phosphorylation, and target gene expression. Unlike Ni(II), Co(II) was ineffective in downregulating the p53 inhibitor MDM4 (HDMX). Co(II)-treated cells continued DNA replication at internal doses that caused massive apoptosis by Ni(II). Apoptosis and the overall cell death by Co(II) were delayed and weaker than by Ni(II). Inhibition of caspases but not programmed necrosis pathways suppressed Co(II)-induced cell death. Knockdown of p53 produced 50%-60% decreases in activation of caspases 3/7 and expression of 2 most highly upregulated proapoptotic genes PUMA and NOXA by Co(II). Overall, p53-mediated apoptosis accounted for 55% cell death by Co(II), p53-independent apoptosis for 20%, and p53/caspase-independent mechanisms for 25%. Similar to H460, normal human lung fibroblasts and primary human bronchial epithelial cells had several times higher accumulation of Co(II) than Ni(II) and showed a delayed and weaker caspase activation by Co(II). Thus, carcinogenicity of soluble Co(II) could be related to high survival of metal-loaded cells, which permits accumulation of genetic and epigenetic abnormalities. High cytotoxicity of soluble Ni(II) causes early elimination of damaged cells and is expected to be cancer suppressive.
Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island 02912.
Samantha E
SE
Green
Michal W
MW
Luczak
Jessica L
JL
Morse
Zachary
Z
DeLoughery
Anatoly
A
Zhitkovich
D001483:Base Sequence; D002273:Carcinogens / Q000493:pharmacokinetics / Q000633:toxicity*; D002460:Cell Line; D003035:Cobalt / Q000493:pharmacokinetics / Q000633:toxicity*; D017931:DNA Primers; D006801:Humans; D008168:Lung / Q000166:cytology / Q000187:drug effects*; D009532:Nickel / Q000493:pharmacokinetics / Q000633:toxicity*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D002273:Carcinogens; D017931:DNA Primers; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D003035:Cobalt; D009532:Nickel
TP53; apoptosis.; cancer; cobalt; nickel; toxicity