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Cadmium induces matrix metalloproteinase-9 expression via ROS-dependent EGFR, NF-кB, and AP-1 pathways in human endothelial cells.
- Source :
-
Toxicology [Toxicology] 2015 Dec 02; Vol. 338, pp. 104-16. Date of Electronic Publication: 2015 Nov 11. - Publication Year :
- 2015
-
Abstract
- Cadmium (Cd), a widespread cumulative pollutant, is a known human carcinogen, associated with inflammation and tumors. Matrix metalloproteinase-9 (MMP-9) plays a pivotal role in tumor metastasis; however, the mechanisms underlying the MMP-9 expression induced by Cd remain obscure in human endothelial cells. Here, Cd elevated MMP-9 expression in dose- and time-dependent manners in human endothelial cells. Cd increased ROS production and the ROS-producing NADPH oxidase. Cd translocates p47(phox), a key subunit of NADPH oxidase, to the cell membrane. Cd also activated the phosphorylation of EGFR, Akt, Erk1/2, and JNK1/2 in addition to promoting NF-кB and AP-1 binding activities. Specific inhibitor and mutagenesis studies showed that EGFR, Akt, Erk1/2, JNK1/2 and transcription factors NF-κB and AP-1 were related to Cd-induced MMP-9 expression in endothelial cells. Akt, Erk1/2, and JNK1/2 functioned as upstream signals in the activation of NF-κB and AP-1, respectively. In addition, N-acetyl-l-cystein (NAC), diphenyleneiodonium chloride (DPI) and apocynin (APO) inhibited the Cd-induced activation of EGFR, Akt, Erk1/2, JNK1/2, and p38 MAPK, indicating that ROS production by NADPH oxidase is the furthest upstream signal in MMP-9 expression. At present, it states that Cd displayed marked invasiveness in ECV304 cells, which was partially abrogated by MMP-9 neutralizing antibodies. These results demonstrated that Cd induces MMP-9 expression via ROS-dependent EGFR->Erk1/2, JNK1/2->AP-1 and EGFR->Akt->NF-κB signaling pathways and, in turn, stimulates invasiveness in human endothelial cells.<br /> (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)
- Subjects :
- Antioxidants pharmacology
Cell Line
Dose-Response Relationship, Drug
Endothelial Cells enzymology
Endothelial Cells pathology
Enzyme Activation
Enzyme Induction
Enzyme Inhibitors pharmacology
Humans
Matrix Metalloproteinase 9 genetics
Mitogen-Activated Protein Kinases metabolism
NADPH Oxidases metabolism
NF-kappa B genetics
Phosphorylation
Proto-Oncogene Proteins c-akt metabolism
RNA Interference
Signal Transduction drug effects
Time Factors
Transcription Factor AP-1 genetics
Transcription, Genetic
Transfection
Cadmium Compounds toxicity
Cell Movement drug effects
Endothelial Cells drug effects
ErbB Receptors metabolism
Matrix Metalloproteinase 9 biosynthesis
NF-kappa B metabolism
Reactive Oxygen Species metabolism
Transcription Factor AP-1 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1879-3185
- Volume :
- 338
- Database :
- MEDLINE
- Journal :
- Toxicology
- Publication Type :
- Academic Journal
- Accession number :
- 26514923
- Full Text :
- https://doi.org/10.1016/j.tox.2015.10.008