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Radiation-induced Apoptosis Mediated by Retinoblastoma Protein¹

Division of Hematology/Oncology, Department of Medicine [C. B., E. P. G.] and Department of Biochemistry and Molecular Biology [S. S.], Lombardi Cancer Center, Georgetown University School of Medicine, Washington, DC 20007-2196

The role of the retinoblastoma gene product, RB, in transmitting the signals of apoptosis is unclear, but RB is considered to be antiapoptotic because RB mediates cell cycle arrest that also can interrupt intracellular signaling pathways leading to apoptosis. -Radiation can cause apoptosis, the process of programmed cell death, via several mechanisms including DNA damage, ceramide production, and the generation of free radical oxygen species. We investigated the effect of RB on radiation-induced apoptosis by restoring normal RB expression in DU-145 prostate cancer cells that have one deleted and one truncated RB gene. DU-145 cells are highly resistant to apoptosis induced either by radiation or by the addition of ceramide. Two independently derived RB-positive DU-145 derivative cell lines underwent apoptosis after irradiation or exposure to the cell permeable C₂-ceramide. Apoptosis in the RB-positive cell lines was not associated with major changes in the cell cycle response to irradiation. RB-mediated apoptosis occurred in the absence of expression of caspases 8, 6, 3, and 7 and without detectable cleavage of poly(ADP)ribose polymerase. However, a specific inhibitor of serine proteases, Na-p-Tosyl-L-lysyl- chloromethyl ketone, inhibited radiation-induced apoptosis in DU-145 cells expressing RB. Radiation-induced apoptosis was preceded by an increase in JUN protein expression and accompanied by activation of the stress-related JUN kinase. Our data show that RB is proapoptotic in DU-145 cells and acts upstream of JUN expression and JNK activation.

¹ Supported by Research Grants CA57178 (to E. P. G.) and CA61774 (to S. S.) from the National Cancer Institute, Grant BE-275 from The American Cancer Society (to S. S.), and an award from the CaPCURE Foundation. The Lombardi Cancer Center Flow Cytometry Core is supported by Grant CA51008 from the National Cancer Institute.

² To whom requests for reprints should be addressed, at Lombardi Cancer Center, 3800 Reservoir Road, NW, Washington, DC 20007-2197. Phone: (202) 687-2207; Fax: (202) 784-1229; E-mail: gelmanne@gunet.georgetown.edu.

Received 2/13/98. Accepted 6/ 2/98.

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