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  • Title: Colistin-induced autophagy and apoptosis involves the JNK-Bcl2-Bax signaling pathway and JNK-p53-ROS positive feedback loop in PC-12 cells.
    Author: Lu Z, Miao Y, Muhammad I, Tian E, Hu W, Wang J, Wang B, Li R, Li J.
    Journal: Chem Biol Interact; 2017 Nov 01; 277():62-73. PubMed ID: 28842171.
    Abstract:
    Our recent study demonstrated neurotoxicity of colistin-induced autophagy and apoptosis in PC-12 cells, and that autophagy reached peak level at 12 h. In this study, we scrutinized the role of JNK in colistin-induced neurotoxicity and demonstrated the relationship among JNK, p53 and ROS in colistin treated PC-12 cells. Colistin-induced autophagy and apoptosis by JNK inhibition/activation were examined by western blotting, electron microscopy, and immunofluorescence/fluorescence microscopy. The results indicated that colistin induced JNK activation reached peak level at 12 h, while the highest levels of p-Bcl2/Bcl2 were observed at 12 h and Bax/Bcl2 significantly increased in a time-dependent manner. In PC-12 cells, inhibition of JNK by SP600125 (JNK inhibitor) resulted in significantly lower levels of autophagy upon colistin treatment, depending on the expression levels of Beclin1, LC3-II, p62 degradation and reduction in the number of autophagic vacuoles. In contrast, anisomycin pretreatment PC-12 cells led to upregulated autophagy. Especially, the highest levels of Beclin1 and p-Bcl2/Bcl2 were observed at 6 h, and Bax/Bcl2, cleaved-caspase3 and cleaved-PARP significantly increased in a time-dependent manner. The results revealed that JNK activation mediated autophagy and apoptosis related to Beclin1-Bcl2 and Bax-Bcl2 complex in colistin-treated PC-12 cells. Silencing of p53 by siRNA before colistin treatment substantially reduced ROS production and transactivated JNK in PC-12 cells. Moreover, activation of JNK increased ROS generation in PC-12 cells. In conclusion, colistin-induced autophagy and apoptosis is correlated to JNK-Bcl2-Bax signaling pathway, and an interaction effect found between intracellular ROS level and JNK-p53 signaling pathway in apoptosis.
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