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.
['Jo|Chulman|C|', 'Koh|Young Ho|YH|']
D053829:Amyloid Precursor Protein Secretases D000818:Animals D000975:Antioxidants D001253:Astrocytes D015820:Cadherins D002104:Cadmium D019256:Cadmium Chloride D002121:Calcium Channel Blockers D002460:Cell Line D004789:Enzyme Activation D007700:Kinetics D020935:MAP Kinase Signaling System D008562:Membrane Glycoproteins D016877:Oxidants D010446:Peptide Fragments D011480:Protease Inhibitors D047428:Protein Kinase Inhibitors D059748:Proteolysis D034622:RNA Interference D034741:RNA, Small Interfering
Cadmium Cadmium N-cadherin γ-Secretase Cd N-cad/CTF2 ERK JNK ROS Jun N-terminal kinase N-cadherin c-terminal fragment 2 cadmium extracellular signal-activated protein kinase reactive oxygen species