Choi Y K, Kim Y S, Choi I Y, Kim S-W, Kim W-K
College of Pharmacy, Seoul National University, Seoul, Republic of Korea.
Free Radic Res. 2008 Jun;42(6):544-53. doi: 10.1080/10715760802146062.
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.
25-羟基胆固醇（25-OH-chol）可诱导多种细胞类型发生凋亡。本研究调查了线粒体依赖性凋亡信号分子在25-OH-chol处理的PC12细胞死亡过程中可能发挥的作用。25-OH-chol增加了活性氧的产生并打开了线粒体通透性转换孔，导致细胞色素c释放，随后激活了caspase-9和-3。25-OH-chol诱导了c-Jun氨基末端激酶（JNK）和糖原合酶激酶-3β（GSK-3β）的激活。JNK抑制剂SP600125减弱了caspase-9和-3的激活，并减少了25-OH-chol诱导的细胞死亡。GSK抑制剂SB415286和SB216763显著下调JNK活性，并减弱了25-羟基胆固醇的细胞毒性。然而，SP600125并未改变GSK-3β的活性。结果表明，25-OH-chol通过激活GSK-3β并随后上调JNK诱导细胞死亡。对GSK-3β-JNK-caspase信号通路进行药理学干预可能有助于降低氧化甾醇的细胞毒性。
