Molecular mechanisms of cadmium carcinogenesis: The potential roles of lipid peroxidation, oncogene activation and metallothionein expression

Abstract

Cadmium is a potent metallic toxin and carcinogen. The metallothionein gene (MT) is highly metal-inducible and encodes for a metal-binding protein, metallothionein (MT), which can protect against the toxic effects of cadmium by sequestration of the metal. The molecular processes involved in cadmium carcinogenesis were examined. Levels of oxidative damage (lipid peroxidation) and the acute activation of proto-oncogenes c-myc and c-jun by cadmium in vitro and the effect of MT gene preactivation on these effects were studied. A low level of cadmium was able to induce expression of the c-myc and c-jun oncogenes and subsequently transform cultured cells. Cadmium caused strain-dependent oxidative damage in vivo in the liver, kidney and testes of mice. Levels of lipid peroxidation were higher in the testes of NFS mice, a strain known to be more susceptible to cadmium toxicity. MT protein preinduction by zinc prevented cadmium-induced lipid peroxidation. This was more marked in BALB/c mice, a strain resistant to the toxic effects of cadmium. Acute in vitro cadmium exposure was an effective inducer of expression of the c-myc and c-jun proto-oncogenes in rat L6 myoblasts; preexposure to zinc effectively repressed their transcriptional induction by cadmium. Chronic low dose cadmium exposure of L6 cells was a potent initiator of transformation. Low dose cadmium-transformed L6 cells, when inoculated into nude mice, produced tumors that were more malignant and had significantly higher growth rates and sizes than untreated control cells. Transformation induced by cadmium was associated with a chronic downregulation of c-myc and c-jun. However, lipid peroxidation was not associated with the increased expression of these oncogenes. Cadmium was an effective initiator of oxidative damage, proto-oncogene activation and L6 transformation. MT expression was associated with protection from acute cadmium toxicity in vitro and in vivo, and prevention of cadmium-induced oncogene activation. MT may thus be intimately involved in the molecular mechanisms of cadmium carcinogenesis.