2,5-Hexanedione induces autophagic death of VSC4.1 cells via a PI3K/Akt/mTOR pathway
2,5-Hexanedione induces autophagic death of VSC4.1 cells via a PI3K/Akt/mTOR pathway
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DOI：
10.1039/c7mb00001d
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发表时间：
2017-10-01
影响因子：
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通讯作者：
Piao, Fengyuan
中科院分区：
文献类型：
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作者：
Guan, Huai;Piao, Hua;Piao, Fengyuan
2,5-己二酮 (HD) 是正己烷的一种重要生物活性代谢物，可介导母体化合物的神经毒性。越来越多的证据表明，过度激活的自噬可导致自噬性神经元死亡；然而，过度自噬是否与 HD 诱导的神经毒性有关仍不清楚。为了研究HD对自噬的影响并找出其潜在机制，我们分别用5、15和25 mM HD处理VSC4.1细胞24小时。我们的结果表明，HD 以剂量依赖性方式诱导 VSC4.1 细胞过度自噬，而且，在 PI3K 激活剂或 Akt 激活剂或 mTOR 激活剂存在下，过度激活的自噬显着减轻。这些结果表明 HD 通过抑制 PI3K/Akt/mTOR 信号通路诱导 VSC4.1 细胞过度自噬。 LDH 测定表明，HD 导致 VSC4.1 细胞死亡浓度依赖性增加，而使用自噬抑制剂 PIK-III 可以显着减少这种死亡。这些结果还表明HD通过信号通路诱导VSC4.1细胞的自噬性死亡。
2,5-Hexanedione (HD) is an important bioactive metabolite of n-hexane, which mediates the neurotoxicity of the parent compound. Increasing evidence suggests that over-activated autophagy can lead to autophagic neuronal death; however, whether the excessive autophagy is involved in HD-induced neurotoxicity remains unknown. To investigate the effect of HD on autophagy and to find its underlying mechanism, we respectively treated VSC4.1 cells with 5, 15 and 25 mM HD for 24 h. Our results show that HD induced excessive autophagy of VSC4.1 cells in a dose-dependent manner, also, the over-activated autophagy was significantly mitigated in the presence of PI3K activator or Akt activator or mTOR activator. These results indicate that HD induces excessive autophagy of VSC4.1 cells by repressing the PI3K/Akt/mTOR signaling pathway. LDH assay showed that HD contributed to a concentration dependent increase in VSC4.1 cell death, which was significantly reduced by the administration of PIK-III, an autophagy inhibitor. These results also indicate that HD induces autophagic death of VSC4.1 cells via the signaling pathway.