Cadmium-induced up-regulation of aldo-keto reductase 1C3 expression in human nasal septum carcinoma RPMI-2650 cells: Involvement of reactive oxygen species and phosphatidylinositol 3-kinase/Akt.

Cadmium is a well-known toxic metal and occupational exposure to it is associated with lung cancer. In probing the possible non-genotoxic molecular targets of cadmium-induced nasal toxicity, we performed an mRNA differential display analysis for cadmium-treated human nasal septum carcinoma RPMI-2650 cells. Cadmium (≥ 0.5 μM) inhibited the cell proliferation. The intracellular ROS levels were induced by cadmium treatment. In addition, cadmium elicited the AKR1C3 expression. The cadmium-induced increase in AKR1C3 protein levels was suppressed by N-acetylcysteine (NAC) and, to a lesser extent, PI3K inhibitor (Ly294002). Cells pretreated with Ly294002 were more resistant to cadmium toxicity than control. The increase in AKR1C3 protein level was accompanied by an increase in the nuclear transcription factor Nrf2. Overall, our data suggest that cadmium-induced ROS cause up-regulation of AKR1C3 expression, at least partially via the activation of PI3K-related intracellular signaling pathways, and Nrf2 activation, thereby contributing to an adaptive intracellular response to cadmium toxicity.