Title: Rotenone-induced apoptosis is mediated by p38 and JNK MAP kinases in human dopaminergic SH-SY5Y cells.
Authors: Newhouse, Kathleen; Hsuan, Shih-Ling; Chang, Sandra H; Cai, Beibei; Wang, Yupeng; Xia, Zhengui
Published In Toxicol Sci, (2004 May)
Abstract: Rotenone is a naturally derived pesticide that has recently been shown to evoke the behavioral and pathological symptoms of Parkinson's disease in animal models. Though rotenone is known to be an inhibitor of the mitochondrial complex I electron transport chain, little is known about downstream pathways leading to its toxicity. We used human dopaminergic SH-SY5Y cells to study mechanisms of rotenone-induced neuronal cell death. Our results suggest that rotenone, at nanomolar concentrations, induces apoptosis in SH-SY5Y cells that is caspase-dependent. Furthermore, rotenone treatment induces phosphorylation of c-Jun, the c-Jun N-terminal protein kinase (JNK), and the p38 mitogen activated protein (MAP) kinase, indicative of activation of the p38 and JNK pathways. Importantly, expression of dominant interfering constructs of the JNK or p38 pathways attenuated rotenone-induced apoptosis. These data suggest that rotenone induces apoptosis in the dopaminergic SH-SY5Y cells that requires activation of the JNK and p38 MAP kinases and caspases. These studies provide insights concerning the molecular mechanisms of rotenone-induced apoptosis in neuronal cells.
PubMed ID: 14976342
MeSH Terms: Apoptosis/drug effects*; Caspases/adverse effects; Caspases/drug effects; Caspases/metabolism; Cell Line, Tumor; Chlorpyrifos/toxicity; Humans; JNK Mitogen-Activated Protein Kinases/adverse effects; JNK Mitogen-Activated Protein Kinases/drug effects; JNK Mitogen-Activated Protein Kinases/metabolism; MAP Kinase Kinase 4; Mitogen-Activated Protein Kinase Kinases/adverse effects; Mitogen-Activated Protein Kinase Kinases/drug effects; Mitogen-Activated Protein Kinase Kinases/metabolism; Receptors, Dopamine/drug effects*; Receptors, Dopamine/genetics; Receptors, Dopamine/metabolism; Rotenone/chemistry; Rotenone/toxicity*; Signal Transduction/drug effects; Transfection/methods; p38 Mitogen-Activated Protein Kinases/adverse effects*; p38 Mitogen-Activated Protein Kinases/drug effects; p38 Mitogen-Activated Protein Kinases/metabolism