抄録
While p53 is known to play a key role in apoptosis induced by ionizing radiation (IR), p53 mutation was reported in more than 50% of tested cancer cells. Many of these cancers, despite the loss of p53 function, are still responsive to radiotherapy, suggesting a p53-independent action of IR. To explore its underlying mechanism, human U937 leukemic cells which have a p53-null mutation were irradiated with -rays at 7 Gy. This treatment resulted in a cell death, which was accompanied by an elevation in cellular ROS levels. The cell death was consistently reversed by the exogenous application of catalase, suggesting that ROS act as death mediators. IR also induced the mitochondrial permeability transition (MPT), and inhibitors for either the MPT or mitochondrial respiratory chain attenuated the IR-induced ROS production. This suggests that the ROS were induced in mitochondria in a MPT-dependent manner. To determine a signaling component upstream of the mitochondrial events, this study focused on JNK because the lethal dose of IR efficiently activated JNK. It was also found that a JNK-specific inhibitor SP600125 suppresses the ability of IR to induce MPT, ROS, and cell death. Overall, the JNK-dependent mitochondrial ROS production appears to be critical for the p53-independent action of IR.
