J Korean Neurol Assoc.
2011 Nov;29(4):317-325.
Effect of Extracellular Signal-Regulated Kinase Inhibition on Oxysterol 7-Ketocholesterol-Induced Apoptosis
- Affiliations
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- 1Department of Neurology, Seoul Veterans Hospital, Seoul, Korea.
- 2Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Korea. leecs@cau.ac.kr
Abstract
- BACKGROUND
Defects in mitochondrial function have been shown to participate in the induction of neuronal cell injury. The extracellular-signal-regulated kinase (ERK) signaling pathway plays a crucial role in almost all cell functions, including proliferation, differentiation, survival, and death. However, the effect of ERK inhibition on oxysterol-induced apoptosis remains uncertain.
METHODS
This study assessed the effect of ERK inhibition on the apoptotic effect of 7-ketocholesterol.
RESULTS
Treatment with 7-ketocholesterol increased phosphorylated-ERK1/2 levels in differentiated PC12 cells, while the total amount of ERK was not altered. 7-Ketocholesterol decreased Bid and Bcl-2 levels, increased Bax and p53 levels, and promoted cytochrome c release, which elicits the activation of caspases (-8, -9, and -3), nuclear damage, and cell death. ERK and farnesyltransferase inhibitors inhibited the 7-ketocholesterol-induced phosphorylation of ERK1/2, activation of apoptosis-related proteins, and cell death in PC12 cells.
CONCLUSIONS
The ERK and farnesyltransferase inhibitors, which did not exhibit toxicity, may inhibit the 7-ketocholesterol toxicity on differentiated PC12 cells by suppressing the activation of the caspase-8-dependent pathway as well as activation of the mitochondria-mediated cell-death pathway, leading to the activation of caspases. The inhibition of ERK may confer a beneficial protective effect against the neuronal cell injury induced by cholesterol oxidation products.
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