Role of the ceramide-signaling pathways in ionizing radiation-induced apoptosis.
Ionizing radiations (IR) exposure leads to damage on several cellular targets. How signals from different targets are integrated to determine the cell fate remains a controversial issue. Understanding the pathway(s) responsible(s) for the cell killing effect of the IR exposure is of prime importance in light of using radiations as anticancer agent or as diagnostic tool. In this study, we have established that IR-induced cell damage initiates two independent signaling pathways that lead to a biphasic intracellular ceramide increase. A transitory increase of ceramide is observed within minutes after IR exposure as a consequence of DNA damage-independent acid sphingomyelinase activation. Several hours after irradiation, a second wave of ceramide accumulation is observed depending on the DNA damage-dependent activation of ceramide synthase, which requires a signaling pathway involving ATM. Importantly, we have demonstrated that the late ceramide accumulation is also dependent on the first one and is rate limiting for the apoptotic process induced by IR. In conclusion, our observations suggest that ceramide is a major determinant of the IR-induced apoptotic process at the cross-point of different signal transduction pathways.
Vit
Jean-Philippe
JP
1UPR 2169 CNRS, Institut Gustave Roussy IFR 54, 39 rue Camille Desmoulins, 94805 Villejuif Cedex, France.
Rosselli
Filippo
F
D017209:Apoptosis / Q000528:radiation effects*; D064007:Ataxia Telangiectasia Mutated Proteins; D020169:Caspases / Q000502:physiology; D018797:Cell Cycle Proteins; D002460:Cell Line; D002518:Ceramides / Q000502:physiology*; D004249:DNA Damage; D004268:DNA-Binding Proteins; D006801:Humans; D009542:Niemann-Pick Diseases / Q000235:genetics; D010088:Oxidoreductases / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D025521:Tumor Suppressor Proteins
D018797:Cell Cycle Proteins; D002518:Ceramides; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; D010088:Oxidoreductases; C108138:dihydroceramide desaturase; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D020169:Caspases