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Suppression of Bcl-2 Messenger RNA Production May Mediate Apoptosis after Ionizing Radiation, Tumor Necrosis Factor , and Ceramide¹

Department of Radiation and Cellular Oncology [M. C., R. R. W.], Department of Pathology, Committee on Immunology [J. Q.], and Department of Medicine and Howard Hughes Institute [C. T.], University of Chicago, Chicago, Illinois 60637; Department of Radiation Therapy, Memorial Sloan-Kettering Cancer Center, New York, New York 10021 [Z. F.]; and Laboratory of Pharmacology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115 [D. W. K.]

Recent studies have proposed that tumor necrosis factor (TNF-) and ionizing radiation induce apoptosis by activating hydrolysis of sphingomyelin to ceramide. Bcl-2 and a related gene, Bcl-X, inhibit several forms of apoptosis. Herein, we report that internucleosomal DNA fragmentation, characteristic of apoptosis and induced by ionizing radiation, is accompanied by concomitant decreases in Bcl-2 and Bcl-X mRNA levels in HL-60 and U-937 human leukemia cells. Apoptotic DNA fragmentation after exposure to TNF- and C₂-ceramide was also associated with down-regulation of Bcl-2 mRNA in HL-60 and U-937 cells, while Bcl-X mRNA production was unaffected. These results suggest that modulation of Bcl-2 gene expression may be a target for ceramide-mediated apoptosis following exposure to ionizing radiation and TNF-. Changes in Bcl-2 expression may be the basis for the interactive killing observed between radiation and TNF- in some human and tumor cells.

¹ Supported by NIH/National Cancer Institute Grants CA42596 and CA55241.

² To whom requests for reprints should be addressed, at Department of Radiation and Cellular Oncology, University of Chicago, S841 South Maryland Avenue, Box 442, Chicago, IL 60637.

Received 12/22/94. Accepted 1/27/95.

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