Abstract
Exposure of cells to ionizing radiation induces activation of multiple signaling pathways that play critical roles in determining cell fate. However, the molecular basis for cell death or survival signaling in response to radiation is unclear at present. Here, we show opposing roles of the c-jun NH(2)-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) pathways in the mitochondrial cell death in response to ionizing radiation in human cervical cancer cells. Ionizing radiation triggered Bax and Bak activation, Bcl-2 down-regulation, and subsequent mitochondrial cell death. Inhibition of JNK completely suppressed radiation-induced Bax and Bak activation and Bcl-2 down-regulation. Dominant-negative forms of stress-activated protein kinase/extracellular signal-regulated kinase kinase 1 (SEK-1)/mitogen-activated protein kinase kinase-4 (MKK-4) inhibited JNK activation. Radiation also induced phosphoinositide 3-kinase (PI3K) activation. Interestingly, inhibition of PI3K effectively attenuated radiation-induced mitochondrial cell death and increased clonogenic survival. Inhibition of PI3K also suppressed SEK-1/MKK-4 and JNK activation, Bax and Bak activation, and Bcl-2 down-regulation. In contrast, inhibition of p38 MAPK led to enhanced Bax and Bak activation and mitochondrial cell death. RacN17, a dominant-negative form of Rac1, inhibited p38 MAPK activation and increased Bax and Bak activation. Exposure of cells to radiation also induced selective activation of c-Src among Src family kinases. Inhibition of c-Src by pretreatment with Src family kinase inhibitor PP2 or small interfering RNA targeting of c-Src attenuated radiation-induced p38 MAPK and Rac1 activation and enhanced Bax and Bak activation and cell death. Our results support the notion that the PI3K-SEK-1/MKK-4-JNK pathway is required for the mitochondrial cell death in response to radiation, whereas the c-Src-Rac1-p38 MAPK pathway plays a cytoprotective role against mitochondrial cell death.
Highlights
Exposure of cells to ionizing radiation results in the simultaneous activation or down-regulation of multiple signaling pathways that play critical roles in cell type – specific control of survival or death in response to ionizing radiation
Our data show that the phosphoinositide 3-kinase (PI3K)-signal-regulated kinase kinase 1 (SEK-1)/mitogen-activated protein kinase kinase-4 (MKK-4)-Jun NH2-terminal kinase (JNK) pathway is essential for mitochondrial cell death in response to radiation, whereas the c-Src-Rac1-p38 Mitogen-activated protein kinases (MAPK) pathway plays a cytoprotective role against radiation-induced mitochondrial cell death
We found that JNK influences the mitochondrial death pathway because its inhibition leads to a failure in cytochrome c and apoptosis-inducing factor release and subsequent caspase activation triggered by ionizing radiation
Summary
Exposure of cells to ionizing radiation results in the simultaneous activation or down-regulation of multiple signaling pathways that play critical roles in cell type – specific control of survival or death in response to ionizing radiation. JNK and p38 MAPK are weakly activated by growth factors, but respond strongly to stress signals including tumor necrosis factor, interleukin-1, ionizing and UV irradiation, hyperosmotic stress, and chemotherapeutic drugs [6,7,8,9,10,11]. Activation of these kinases is strongly associated with apoptotic cell death induced by stress stimuli. Many reports suggested that JNK or p38 MAPK induces apoptosis by regulating the translocation of Bax from the
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