Cadmium induces N-cadherin cleavage via ERK-mediated γ-secretase activation in C6 astroglia cells.

N-cadherin has known to be involved in tumor progression and metastasis. However, it is still obscure about the signaling pathway involving in the processing of N-cadherin. Thus, we examined which signaling pathway plays a major role in the processing of N-cadherin in C6 glioma cells following treatment of cadmium (Cd), a highly ubiquitous heavy metal. A cleavage product of N-cadherin, N-cad/CTF2 was observed by the treatment of Cd to C6 cells in a time and concentration-dependent manner. The production of N-cad/CTF2 was inhibited by pretreatment of γ-secretase inhibitors or siRNA transfection of nicastrin, indicating that γ-secretase is involved in the cleavage. Interestingly, Cd could activate both ERK and JNK signaling pathways in C6 cells; however, γ-secretase-mediated N-cad/CTF2 production by Cd was completely blocked by MEK1/2 inhibitors PD184352 and U0126, but not by a JNK inhibitor SP600125, demonstrating that the ERK signaling pathway plays a major role in the cleavage. In addition, pretreatment of an antioxidant or Ca²⁺ blocker blocked the production of N-cad/CTF2 by Cd together with the inhibition of ERK1/2 phosphorylation. Collectively, these results suggest that Cd increases intracellular Ca²⁺ or ROS, which induces γ-secretase-dependent N-cad/CTF2 production via the activation of the ERK signaling pathway in C6 glial cells.