25-hydroxycholesterol induces mitochondria-dependent apoptosis via activation of glycogen synthase kinase-3beta in PC12 cells.
25-hydroxycholesterol (25-OH-chol) induces apoptosis in many cell types. The present study investigated the possible involvement of mitochondria-dependent apoptotic signalling molecules in the death of PC12 cells treated with 25-OH-chol. 25-OH-chol increased the production of reactive oxygen species and opened mitochondrial permeability transition pore, resulting in release of cytochrome c and subsequent activation of caspase-9 and -3. 25-OH-chol induced the activation of c-Jun N-terminal kinase (JNK) and glycogen synthase kinase-3beta (GSK-3beta). The JNK inhibitor SP600125 attenuated the activation of caspase-9 and -3 and reduced 25-OH-chol-induced cell death. GSK inhibitors SB415286 and SB216763 significantly down-regulated JNK activity and attenuated the cytotoxicity of 25-hydroxycholesterol. However, SP600125 did not alter the activity of GSK-3beta. The results indicate that 25-OH-chol induces cell death via activation of GSK-3beta and subsequent up-regulation of JNK. Pharmacological intervention of GSK-3beta-JNK-caspase signalling pathway may be useful for the reduction of cytotoxicity of oxysterols.
College of Pharmacy, Seoul National University, Seoul, Republic of Korea.
Y K
YK
Choi
Y S
YS
Kim
I Y
IY
Choi
S-W
SW
Kim
W-K
WK
Kim
D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006888:Hydroxycholesterols / Q000494:pharmacology*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D008954:Models, Biological; D016716:PC12 Cells; D051381:Rats; D015398:Signal Transduction
D000873:Anthracenes; D004791:Enzyme Inhibitors; D006888:Hydroxycholesterols; C432165:pyrazolanthrone; C007997:25-hydroxycholesterol; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; D048670:MAP Kinase Kinase 4; D053148:Caspase 3; D053453:Caspase 9