title: Cadmium induces N-cadherin cleavage via ERK-mediated γ-secretase activation in C6 astroglia cells.
abstract: 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.
authors.affiliation: Division of Brain Diseases, Center for Biomedical Sciences, Korea National Institute of Health, 187 Osongsaengmyeong2(i)-ro, Gangoe-myeon, Cheongwon-gun, Chungcheongbuk-do 363-951, Republic of Korea.
authors.forename: Chulman
authors.initials: C
authors.lastname: Jo
authors.forename: Young Ho
authors.initials: YH
authors.lastname: Koh
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001253:Astrocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism*; D002104:Cadmium / Q000737:chemistry / Q000633:toxicity*; D019256:Cadmium Chloride / Q000037:antagonists & inhibitors / Q000633:toxicity; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D007700:Kinetics; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016877:Oxidants / Q000037:antagonists & inhibitors / Q000633:toxicity*; D010446:Peptide Fragments / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D059748:Proteolysis / Q000187:drug effects; D034622:RNA Interference; D034741:RNA, Small Interfering
chemical_list: D000975:Antioxidants; D015820:Cadherins; D002121:Calcium Channel Blockers; D008562:Membrane Glycoproteins; D016877:Oxidants; D010446:Peptide Fragments; D011480:Protease Inhibitors; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; C413604:nicastrin protein; D002104:Cadmium; D053829:Amyloid Precursor Protein Secretases; D019256:Cadmium Chloride
keywords: Cadmium; Cd; ERK; JNK; Jun N-terminal kinase; N-cad/CTF2; N-cadherin; N-cadherin c-terminal fragment 2; ROS; cadmium; extracellular signal-activated protein kinase; reactive oxygen species; γ-Secretase