Hepatocytes display a compensatory survival response against cadmium toxicity by a mechanism mediated by EGFR and Src

Although the liver is a cadmium-target organ, hepatocyte response involved in its toxicity is not yet elucidated. A link between this heavy metal treatment and Stat3 signaling pathways was examined in primary mouse hepatocytes. We provided evidence of a novel link among NADPH oxidase and Stat3 signaling, mediated by Src, EGFR, and Erk1/2. Cadmium activates NADPH oxidase. ROS produced by this oxidase activates Src, enable that in turn, transactivates EGFR that activates Stat3 in tyrosine, allowing its dimerization. Also, ROS from NADPH oxidase favors ERK1/2 activation that phosphorylates Stat3 in serine, resulting in a compensatory or adaptive survival response such as production of metallothionein-II in short Cd exposure times. However, after 12 h CdCl2 treatment, cell viability diminished in 50%, accompanied by a drastic decrease of metallothionein-II production, and an increase in p53 activation and the pro-apoptotic protein Bax.

► Stat3 is activated by a different route, in which Src kinase is involved. ► Cadmium presented an adaptive response, but finally cells die. ► Metallothionein-II protein production was quantified in response to Cd. ► Hepatocyte primary culture is best system to study signaling by Cd.