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  • Title: Reactive oxygen species-dependent JNK downregulated olaquindox-induced autophagy in HepG2 cells.
    Author: Zhao D, Wang C, Tang S, Zhang C, Zhang S, Zhou Y, Xiao X.
    Journal: J Appl Toxicol; 2015 Jul; 35(7):709-16. PubMed ID: 25042557.
    Abstract:
    Autophagy plays an important role in response to intracellular and extracellular stress to sustain cell survival. However, dysregulated or excessive autophagy may lead to cell death, known as "type II programmed cell death," and it is closely associated with apoptosis. In our previous study, we proposed that olaquindox induced apoptosis of HepG2 cells through a caspase-9 dependent mitochondrial pathway. In this study, we investigated autophagy induced by olaquindox and explored the crosstalk between apoptosis and autophagy in olaquindox-treated HepG2 cells. Olaquindox-induced autophagy was demonstrated by the accumulation of monodansylcadervarine, as well as elevated expression of autophagy-related MAP-LC3 and Beclin 1 proteins. The autophagy inhibitor 3-methyladenine significantly increased the apoptotic rate induced by olaquindox, which was correlated with increased ratio of Bax/Bcl-2. The further studies showed that olaquindox increased the levels of reactive oxygen species (ROS), and antioxidant N-acetyl-L-cysteine (NAC) effectively blocked the accumulation of ROS but failed to block autophagy. Moreover, olaquindox induced the activation of c-Jun N-terminal protein kinase (JNK), and JNK inhibitor SP600125 failed to block autophagy. Instead, olaquindox-induced autophagy was enhanced by NAC or SP600125. Meanwhile, JNK activation was remarkably blocked by NAC, indicating that ROS may be the upstream signaling molecules of JNK activation and involved in the negative regulation of olaquindox-induced autophagy. These results suggest that olaquindox induces autophagy in HepG2 cells and that olaquindox-induced apoptosis can be enhanced by 3-methyladenine. Olaquindox-induced autophagy in HepG2 cells is upregulated by Beclin 1 but downregulated by ROS-dependent JNK.
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