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Ionizing Radiation-induced, Bax-mediated Cell Death Is Dependent on Activation of Cysteine and Serine Proteases¹

Department of Cancer Biology, Lerner Research Institute [B. G., Q. C., S. M., A. A.], and Department of Radiation Oncology, The Cleveland Clinic Foundation [B. G., Q. C., B. E., S. M., A. A.], Cleveland, Ohio 44195

Bcl-2 family proteins and interleukin-1-ß converting enzyme/Caenorhabditis elegans cell death gene-3 (ICE/CED-3) family proteases (caspases) represent the basic regulators of apoptosis. However, the precise mechanism by which they interact is unclear. In this study, we found that -radiation-induced apoptosis of leukemia cells was associated with activation of multiple caspases and bax up-regulation. Membrane changes and caspase activities were suppressed by specific caspase inhibitors. Similarly, the serine protease inhibitors z-Ala-Ala-Asp-cmk (AAD) and tosyl-lysine chloromethyl ketone (TLCK) also prevented caspase activation and poly(ADP-ribose) polymerase cleavage in vivo but had no effect on caspase activity in vitro. TLCK also prevented bax up-regulation as a result of its inhibitory effect on p53 function. Inhibitors of caspases and serine proteases partially prevented cell death, suggesting a caspase involvement in Bax-mediated cell death. We propose an ordering of signaling events in Bax-mediated cell death, including steps upstream and downstream of p53 and bax up-regulation.

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