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J. Biol. Chem., Vol. 278, Issue 11, 9813-9822, March 14, 2003

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Ceramide Increases Oxidative Damage Due to Inhibition of Catalase by Caspase-3-dependent Proteolysis in HL-60 Cell Apoptosis^*

Kazuya Iwai, Tadakazu Kondo, Mitsumasa Watanabe, Takeshi Yabu, Toshiyuki Kitano, Yoshimitu Taguchi^§, Hisanori Umehara^¶, Atsushi Takahashi, Takashi Uchiyama, and Toshiro Okazaki

From the  Departments of Hematology and Oncology and ^¶ Clinical Immunology, Graduate School of Medicine, Kyoto University, 54 Syogoin-Kawaramachi, Sakyo-ku, Kyoto 606-8507 and the ^§ Laboratory of Membrane Biochemistry and Biophysics, Graduate School of Biostudies, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan

We investigated through which mechanisms ceramide increased oxidative damage to induce leukemia HL-60 cell apoptosis. When 5 µM N-acetylsphingosine (C₂-ceramide) or 20 µM H₂O₂ alone induced little increase of reactive oxygen species (ROS) generation as judged by the 2'-7'-dichlorofluorescin diacetate method, 20 µM H₂O₂ enhanced oxidative damage as judged by ROS accumulation, and thiobarbituric acid-reactive substance production after pretreatment with 5 µM C₂-ceramide at least for 12 h. The treatment with a catalase inhibitor, 3-amino-1h-1,2,4-triazole, increased oxidative damage and apoptosis induced by H₂O₂, and in contrast, purified catalase inhibited the enhancement of oxidative damage by H₂O₂ in ceramide-pretreated cells, suggesting that the oxidative effect of ceramide is involved in catalase regulation. Indeed, C₂-ceramide inhibited the activity of immunoprecipitated catalase and decreased the levels of catalase protein in a time-dependent manner. Moreover, acetyl-Asp-Met-Gln-Asp-aldehyde, which dominantly inhibited caspase-3 and blocked the increase of oxidative damage and apoptosis due to C₂-ceramide-induced catalase depletion at protein and activity levels. In vitro, active and purified caspase-3, but not caspase-6, -8, and -9, inhibited catalase activity and induced the proteolysis of catalase protein whereas these in vitro effects of caspase-3 were blocked by acetyl-Asp-Met-Gln-Asp-aldehyde. Taken together, it is suggested that H₂O₂ enhances apoptosis in ceramide-pretreated cells, because ceramide increases oxidative damage by inhibition of ROS scavenging ability through caspase-3-dependent proteolysis of catalase.

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