Initiation of ionizing radiation-induced apoptosis: DNA damage-mediated ordoes ceramide have a role?

Purpose: To critically review the data supporting membrane damage-induced i ncreases in ceramide levels as the primary initiator of ionizing radiation- induced apotosis and to point out that there is compelling evidence support ing the involvement of DNA damage in this process. Conclusions: There is now a significant literature suggesting that irradiat ion of cells can quickly lead to a modest, transitory increase in the level of the putative second messenger ceramide. These results have been used to support the views that membrane damage is the primary trigger for radiatio n-induced apoptosis and that DNA damage is irrelevant to this process. II i s argued, however, that the data are inadequate to support such conclusions because it is questionable whether the induced levels of ceramide are toxi c and because the ceramide hypothesis cannot convincingly explain the delay ed apoptosis, dependent on events such as mitosis, that is shown by many ce ll lines. In contrast, it is suggested that the sensitivity of some cell ty pes to the induction of apoptosis by DNA-targeted radiation damage, the rel ationship between p53 status and radiation response, and the influence of e nzymatic DNA repair capability on susceptibility to apoptosis, ar,sue stron gly that DNA damage is relevant to the triggering of apoptosis.