권소희 (성균관대학교, 현재 Friedrich Miescher Institute for Biomedical Research) | 한빛사논문 > 한빛사

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성균관대학교, 현재 Friedrich Miescher Institute for Biomedical Research

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J. Biol. Chem., First Published on November 6, 2001, doi: 10.1074/jbc.M106699200 Apicidin, a Histone Deacetylase Inhibitor, Induces Apoptosis and Fas/Fas Ligand Expression in Human Acute Promyelocytic Leukemia Cells*

Abstract

So Hee Kwon‡, Seong Hoon Ahn‡, Yong Kee Kim‡, Gyu-Un Bae‡, Jong Woo Yoon‡, Sungyoul Hong§, Hoi Young Lee¶, Yin-Won Lee∥, Hyang-Woo Lee‡ and Jeung-Whan Han‡**

From the ^‡Department of Biochemistry and Molecular Biology, College of Pharmacy and ^§Department of Genetic Engineering, College of Life Science and Natural Resources, Sungkyunkwan University, Suwon 440-746, Korea, ^¶Department of Pharmacology, College of Medicine, Konyang University, Nonsan 320-711, Korea, and ^∥School of Agricultural Biotechnology, Seoul National University, Suwon 441-744, Korea

Abstract
We previously reported that apicidin arrested human cancer cell growth through selective induction of p21^WAF1/Cip1. In this study, the apoptotic potential of apicidin and its mechanism in HL60 cells was investigated. Treatment of HL60 cells with apicidin caused a decrease in viable cell number in a dose-dependent manner and an increase in DNA fragmentation, nuclear morphological change, and apoptotic body formation, concomitant with progressive accumulation of hyperacetylated histone H4. In addition, apicidin converted the procaspase-3 form to catalytically active effector protease, resulting in subsequent cleavages of poly(ADP-ribose) polymerase and p21^WAF1/Cip1. Incubation of HL60 cells with z-DEVD-fmk, a caspase-3 inhibitor, almost completely abrogated apicidin-induced activation of caspase-3, DNA fragmentation, and cleavages of poly(ADP-ribose) polymerase and p21^WAF1/Cip1. Moreover, these effects were preceded by an increase in translocation of Bax into the mitochondria, resulting in the release of cytochrome c and cleavage of procaspase-9. The addition of cycloheximide greatly inhibited activation of caspase-3 by apicidin by interfering with cleavage of procaspase-3 and DNA fragmentation, suggesting that apicidin-induced apoptosis was dependent on de novo protein synthesis. Consistent with these results, apicidin transiently increased the expressions of both Fas and Fas ligand. Preincubation with NOK-1 monoclonal antibody, which prevents the Fas-Fas ligand interaction and is inhibitory to Fas signaling, interfered with apicidin-induced translocation of Bax, cytochrome c release, cleavage of procaspase-3, and DNA fragmentation. Taken together, the results suggest that apicidin might induce apoptosis through selective induction of Fas/Fas ligand, resulting in the release of cytochrome c from the mitochondria to the cytosol and subsequent activation of caspase-9 and caspase-3.

Footnotes

* This work was supported by Kyonggi Pharmaceutical Research Center, Republic of Korea, Grant KPRC-99-KA-1-3.The costs of publication of this article were defrayed in part by the payment of page charges. The 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. Tel.: 82-31-290-7716; Fax: 82-31-292-8800

Published, JBC Papers in Press, November 6, 2001, DOI 10.1074/jbc.M106699200

Received July 17, 2001. Revision received October 29, 2001.

논문정보

형식Research article
게재일2002년 01월 (BRIC 등록일 )
연구진국내 연구진
분야 생명과학 > 생화학
피인용횟수120회 이상 인용된 논문

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