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J. Biol. Chem., Vol. 280, Issue 11, 10509-10515, March 18, 2005

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Cisplatin Inactivation of Caspases Inhibits Death Ligand-induced Cell Death in Vitro and Fulminant Liver Damage in Mice^*

Jin Na Shin, Young Woo Seo¶, Moonil Kim||, Sun-Young Park, Mi-Ja Lee**, Byung Rai Lee, Jae-Wook Oh, Dai-Wu Seol||, and Tae-Hyoung Kim

From the Department of Biochemistry, Anatomy, ^**Pathology, and Medical Science and Engineering Research Center for Resistant Cells, Chosun University School of Medicine, 375 Seosuk-Dong, Dong-Gu, Gwangju, 501-759, Korea, the ^¶Korea Basic Science Institute Gwang-Ju Branch, Chonnam National University 300 Yongbong-Dong, Buk-Gu, Gwang-Ju, 500-757, Korea, and the ^||Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261

Cisplatin is a platinum-containing chemotherapeutic drug that has been widely used to treat various human cancers. It acts by forming inter- and intracross-links of DNA, which is believed to be a major cause for its therapeutic efficacy. However, little attention has been paid to the effect of cisplatin on death ligand-induced cell death. Here we demonstrate that cisplatin inhibits death ligand-induced cell death in cell lines in a p53-independent manner. This inhibitory effect of cisplatin on cell death is direct, whereby cisplatin forms a complex with caspases leading to their inactivation. The cisplatin-caspase complex is reversed by the addition of reducing agent dithiothreitol, and caspase activity is regained. In addition, cisplatin shows a death-inhibition effect in in vivo animal models of fulminant liver damage induced by Fas activation and lipopolysaccharide-induced liver shock mediated by tumor necrosis factor-. Together, we demonstrate that cisplatin inhibits cell death induced by death ligands in cell lines and in mice through caspase inactivation.

Received for publication, December 9, 2004

^* This work was supported by Grant R13-2003-009-01002-0 from the Research Center for Resistant Cells (Medical and Engineering Research Center at Chosun University School of Medicine) funded by the Korea Science and Engineering Foundation (to T.-H. K. and J.-W. O.) and by a Grant R05-2003-000-10430-0 from the Korea Science and Engineering Foundation (to T.-H. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Rm. 2205, 2nd Floor of New Medical Bldg., Dept. of Biochemistry and Molecular Biology, Chosun University School of Medicine, 375 Seosuk-Dong, Dong-Gu, Gwangju, 501-759, Korea. Tel.: 82-62-230-6294; Fax: 82-62-226-4165; E-mail: thkim65{at}mail.chosun.ac.kr.

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