Apicidin, a histone deacetylase inhibitor, induces apoptosis and Fas/Fas ligand expression in human acute promyelocytic leukemia cells
Apicidin, a histone deacetylase inhibitor, induces apoptosis and Fas/Fas ligand expression in human acute promyelocytic leukemia cells
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DOI：
10.1074/jbc.m106699200
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发表时间：
2002-01-18
影响因子：
4.8
通讯作者：
Han, JW
中科院分区：
文献类型：
--
作者：
Kwon, SH;Ahn, SH;Han, JW
我们先前报道，apicidin通过选择性地诱导p21(WAF1/Cip1)抑制人类癌细胞的生长。本研究探讨了apicidin对HL60细胞的诱导凋亡作用及其机制。用apicidin处理HL60细胞后，活细胞数以剂量依赖的方式减少，DNA片段化、核形态变化和凋亡体形成增加，同时伴随着高乙酰化的组蛋白H4的逐渐积累。此外，apicidin将原天冬氨酸氨基转移酶-3转化为催化活性的效应型蛋白酶，导致多聚(ADP-核糖)聚合酶和p21(WAF1/Cip1)随后的裂解。用caspase-3抑制剂z-DEVD-fmk孵育HL60细胞，几乎完全消除了apicidin诱导的caspase-3激活、DNA断裂和多聚(ADP-核糖)聚合酶和p21(WAF1/Cip1)的断裂。此外，在这些作用之前，Bax移位到线粒体中的增加，导致细胞色素c的释放和原天冬氨酸氨基转移酶-9的切割。放线菌素可显著抑制apicidin对caspase-3的激活，干扰原-aspase-3的裂解和DNA片段化，提示apicidin诱导的细胞凋亡依赖于从头蛋白的合成。与这些结果一致的是，Apicidin瞬时增加了Fas和Fas配体的表达。用NOK-1单抗预先孵育，可以阻止Fas-Fas配体的相互作用，抑制Fas信号转导，干扰蜂毒诱导的Bax转位、细胞色素c释放、原天冬氨酸酶-3的裂解和DNA片段化。综上所述，这些结果表明，apicidin可能通过选择性地诱导Fas/Fas配体，导致细胞色素c从线粒体释放到胞浆，进而激活caspase-9和caspase-3，从而诱导细胞凋亡。
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 hyper-acetylated 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.