LOSS OF CERAMIDE PRODUCTION CONFERS RESISTANCE TO RADIATION-INDUCED APOPTOSIS

Ionizing radiation mediates cell death, in part, through chromosomal d amage following one or more cell divisions, X-rays also induce program med cell death (apoptosis) in some cell types both in vitro and in viv o, Both neutral and acidic sphingomyelinases, which generate the lipid second messenger ceramide, are reported to induce apoptosis following ionizing radiation and other death signals such as tumor necrosis fac tor Lu and Fas ligand, Herein we report that a loss of ceramide produc tion from a neutral sphingomyelinase generates a radioresistant phenot ype as measured by a marked decrease in apoptosis, A WEHI-231 subline made deficient in ceramide production was found to be resistant to apo ptosis compared with the parental subline following treatment with X-r ays, The resistant subline underwent two to three subsequent cell divi sions following X-irradiation, confirming that X-rays induce cell deat h through both mitotic and apoptotic mechanisms, These data suggest th at loss of ceramide production following X-rays represents an extranuc lear mechanism for the development of radioresistance, Modulation of e xtranuclear signals may increase tumor cell killing following radiatio n and represent new cellular targets for cancer therapy.