Effect of Extracellular Signal-Regulated Kinase Inhibition on Oxysterol 7-Ketocholesterol-Induced Apoptosis.
- Author:
Jung Yun HWANG
1
;
Seon Wha LEE
;
Jeong Ho HAN
;
Doo Eung KIM
;
Chung Soo LEE
Author Information
1. Department of Neurology, Seoul Veterans Hospital, Seoul, Korea.
- Publication Type:Original Article
- Keywords:
7-Ketocholesterol;
ERK inhibition;
PC12 cells;
Apoptosis-related proteins;
Cell death
- MeSH:
Animals;
Apoptosis;
Caspases;
Cell Death;
Cholesterol;
Cytochromes c;
Farnesyltranstransferase;
Ketocholesterols;
Neurons;
PC12 Cells;
Phosphorylation;
Phosphotransferases;
Proteins
- From:Journal of the Korean Neurological Association
2011;29(4):317-325
- CountryRepublic of Korea
- Language:Korean
-
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.
