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Papers In Press, published online ahead of print January 2, 2003
Department of Hematology and Oncology, Kyoto University, Graduate School of Medicine, Kyoto 606-8507
Corresponding Author: toshiroo{at}kuhp.kyoto-u.ac.jp
It is poorly understood how caspase-3 is involved in the generation of oxidative damage in ceramide-induced apoptosis. N-acetylsphingosine (C2-ceramide) induced a time- and dose-dependent increase of oxidative damage as judged by lipid peroxidation. Since C2-ceramide synergistically enhanced the amount of ROS generated by hydrogen peroxide (H2O2), not only the generation of ROS but also the inhibition of ROS scavenging system seemed to engage in ceramide-increased oxidative damage. Indeed, C2-ceramide inhibited the activity of catalase in a time- and dose-dependent manner, and a catalase inhibitor 3-amino-1h-1, 2, 4-triazole (ATZ) enhanced the ceramide-induced oxidative damage and apoptosis whereas the addition of purified catalase suppressed them. In addition, a synthetic caspase-3 inhibitor acetyl-Asp-Met-Gln-Asp-aldehyde (DMQD-CHO) reduced C2-ceramide-induced oxidative damage and apoptosis by restoring the inhibited catalase activity, suggesting that ceramide-activated caspase-3 increased oxidative damage by inhibiting catalase activity. The treatment with C2-ceramide depleted catalase at mRNA and protein synthesis levels, while DMQD-CHO restored ceramide-depleted catalase at both levels. Moreover, co-immunoprecipitation and confocal microscopy using anti-caspase-3 and/or anti-catalase antibodies revealed the collocalization of caspase-3 and catalase in the cells. In vitro work showed that active caspase-3, but not caspase-6, -8 and -9, inhibited catalase activity and induced the cleavage of catalase protein, indicating a direct interaction between caspase-3 and catalase. Taken together, these results suggest that catalase function is depleted by caspase-3 not only indirectly at mRNA and protein synthesis levels but also, at least in part, directly at enzyme activating step in ceramide-induced apoptosis.
J. Biol. Chem, 10.1074/jbc.M201867200
Submitted on February 25, 2002
Revised on January 2, 2003
Accepted on January 2, 2003
Ceramide increases oxidative damage due to inhibition of catalase by caspase-3-dependent proteolysis in HL-60 cell apoptosis
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