Cell and Tissue Signaling

Tuesday, October 18, 2005 3:00 PM-5:00 PM Exhibit Hall

(PP270) JNK-dependent ROS production in mitochondria: its role in gamma-ray-induced cell death.

Yang, Hyun Sook1, Lee, Seung Bum1, Um, Hong-Duck*,1, 1 Laboratory of Radiation Tumor Physiology, Seoul, Korea, Korea

ABSTRACT- Ionizing radiation (IR) therapy is one of the most common cancer treatments. While it is well established that p53 is essential for the IR-induced apoptosis, p53 is reportedly mutated in more than 50% of tested cancer cells. Many of these cancers, despite the loss of p53 function, are still responsive to radiotherapy, suggesting that IR can induce cell death in a p53-independent manner. To investigate the mechanism of this phenomenon, human U937 leukemic cells which have a p53-null mutation were irradiated with gamma-rays at 7 Gy. This treatment resulted in a cell death, which was accompanied by an elevation in cellular levels of reactive oxygen species (ROS). This type of cell death was reversed by the exogenous application of catalase, suggesting that ROS mediate lethality by IR. IR was found to induce the mitochondrial permeability transition (MPT) in this system. Moreover, the IR-induced ROS accumulation was attenuated by the use of either mitochondrial respiration inhibitors, such as rotenone and antimycin A or a MPT inhibitor cyclosporin A. This suggests that the ROS were induced in mitochondria in a MPT-dependent manner. To determine an upstream signaling component responsible for the mitochondrial event, this study focused on JNK because the lethal dose of IR efficiently activated JNK. The inhibition of this enzyme using its specific inhibitor SP600125 suppressed the ability of IR to induce MPT, ROS, and cell death. Overall, the JNK-dependent mitochondrial ROS production appears to be a critical event for the p53-independent action of IR.

Key words: gamma-ray, ROS, JNK, mitochondria

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2005 RRS