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Departments of Pathology [S. J. C., J. Q.] and Radiation and Cellular Oncology [E. N., M. A. B., R. R. W.], Division of Biological Sciences, University of Chicago and the Pritzker School of Medicine, Chicago, Illinois 60637, and Laboratory of Pharmacology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115 [D. W. K.]
Ionizing radiation mediates cell death, in part, through chromosomal damage following one or more cell divisions. X-rays also induce programmed cell death (apoptosis) in some cell types both in vitro and in vivo. 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 factor 
and Fas ligand. Herein we report that a loss of ceramide production from a neutral sphingomyelinase generates a radioresistant phenotype as measured by a marked decrease in apoptosis. A WEHI-231 subline made deficient in ceramide production was found to be resistant to apoptosis compared with the parental subline following treatment with X-rays. The resistant subline underwent two to three subsequent cell divisions following X-irradiation, confirming that X-rays induce cell death through both mitotic and apoptotic mechanisms. These data suggest that loss of ceramide production following X-rays represents an extranuclear mechanism for the development of radioresistance. Modulation of extranuclear signals may increase tumor cell killing following radiation and represent new cellular targets for cancer therapy.
1 Supported by NIH Grants GM07183, 5-R01-CA41068, 5-R01-CA42596, PO1-CA-19266, and HD-07009.
2 To whom requests for reprints should be addressed, at Department of Radiation Oncology, University of Chicago Hospitals. 5841 South Maryland Avenue, MC 1089. Chicago, IL 60637. Phone: (312) 702-0817; Fax: (312) 702-1968; E-mail: rrw@rover.uchicago.edu.
Received 10/ 3/96. Accepted 1/27/97.
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