Abstract
Since radiation-induced caspase-dependent apoptosis and ROS generation were partially prevented by HSP25 overexpression, similar to the treatment of control cells with antioxidant agents such as DPI and tiron, questions arise whether radiation-mediated ROS generation contributes to the apoptotic cell death and also whether HSP25 overexpression can reduce ROS mediated apoptotic cell death. In the present study, radiation-induced cytochrome c release from mitochondria and activation of caspases accompanied by a decrease of mitochondrial membrane potential in Jurkat T cells were shown to be inhibited by mitochondrial complex I inhibitor rotenone, suggesting that mitochondrial ROS might be important in radiation-induced caspase-dependent apoptosis. When HSP25 was overexpressed, effects similar to the treatment of cells with the antioxidants were obtained, indicating that HSP25 suppressed radiation-induced mitochondrial alteration that resulted in apoptosis. Furthermore, activation of p38 MAP kinase by radiation was associated with radiation-induced cell death and ROS production and PKCδ was an upstream molecule for p38 MAP kinase activation, ROS generation and subsequent caspase-dependent apoptotic events. However, in the HSP25 overexpressed cells, the above-described effects were blocked. In fact, radiation-induced membrane translocation of PKCδ and tyrosine phosphorylation were inhibited by HSP25. Based on the above data, we suggest that HSP25 downregulates PKCδ, which is a key molecule for radiation-induced ROS generation and mitochondrial-mediated caspase-dependent apoptotic events.
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Acknowledgements
We thank KJ Kim for his excellent technical assistance. This work was supported by Korea Institute of Science and Technology Evaluation and Planning (KISTEP) and Ministry of Science and Technology (MOST), Korean government, through its National Nuclear Technology Program.
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Lee, YJ., Lee, DH., Cho, CK. et al. HSP25 inhibits radiation-induced apoptosis through reduction of PKCδ-mediated ROS production. Oncogene 24, 3715–3725 (2005). https://doi.org/10.1038/sj.onc.1208440
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DOI: https://doi.org/10.1038/sj.onc.1208440
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