Open AccessTranscriptional and translational regulation of COX-2 expression by cadmium in C6 glioma cells
Author(s) -
Yu-Kyoung Park,
Huixiao Hong,
ByeongChurl Jang
Publication year - 2012
Publication title -
international journal of molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.048
H-Index - 90
eISSN - 1791-244X
pISSN - 1107-3756
DOI - 10.3892/ijmm.2012.1052
Subject(s) - cycloheximide , tunicamycin , mg132 , downregulation and upregulation , cadmium , mapk/erk pathway , protein kinase a , biology , kinase , microbiology and biotechnology , chemistry , biochemistry , apoptosis , protein biosynthesis , proteasome inhibitor , unfolded protein response , gene , organic chemistry
High exposure to cadmium is a risk factor for many neuronal diseases. Overexpression of cyclooxygenase (COX)-2 is linked to many neuroinflammatory and neoplastic diseases. We, herein, investigated the effect of cadmium on the expression of COX-2 in C6 rat glioma cells. Treatment with cadmium sulfate (cadmium) increased the expression of COX-2 mRNA. Remarkably, cadmium treatment further increased expression of not only the N-glycosylated COX-2 protein of 72 kDa but also the unglycosylated COX-2 of 66 kDa, as assessed by the unglycosylated COX-2 induced by tunicamycin or glucosamine, known inhibitors of COX-2 N-glycosylation. Of note, when translation was blocked in the presence of cycloheximide (CHX), levels of both N-glycosylated and unglycosylated COX-2 proteins induced by cadmium rapidly declined but the decline was prevented by MG132, a 26S proteasomal inhibitor. However, in the absence of CHX, cadmium induced and maintained expression of the unglycosylated COX-2 proteins. Pharmacological inhibition studies importantly demonstrated that the cadmium-mediated COX-2 transcriptional upregulation in C6 cells was not shown by exogenous glutathione (GSH) supplementation or treatment with inhibitors of extracellular signal-regulated protein kinase-1/2 (ERK-1/2), p38 MAPK and c-Jun N-terminal protein kinase-1/2 (JNK-1/2), respectively. Expression of COX-2 was not noted in C6 cells exposed to other heavy metals (cobalt or manganese). These results demonstrate that cadmium specifically induces expression of COX-2 through both transcriptional and co-translational (N-glycosylation) regulation in C6 cells in which the cadmium-induced COX-2 transcriptional upregulation is closely related to oxidative stress-dependent activation of the family of MAPKs and the cadmium-induced expression of both N-glycosylated and unglycosylated COX-2 proteins is proteasome- and translation-dependent.