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-3β (GSK-3β). 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-3β. The results indicate that 25-OH-chol induces cell death via activation of GSK-3β and subsequent up-regulation of JNK. Pharmacological intervention of GSK-3β-JNK-caspase signalling pathway may be useful for the reduction of cytotoxicity of oxysterols.
|Number of pages||10|
|Journal||Free Radical Research|
|Publication status||Published - 2008 Jun|
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