4-hydroxynonenal induces apoptosis via caspase-3 activation and cytochrome c release
4-hydroxynonenal induces apoptosis via caspase-3 activation and cytochrome c release
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DOI：
10.1021/tx000186f
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发表时间：
2001-08-01
影响因子：
4.1
通讯作者：
Marnett, LJ
中科院分区：
文献类型：
--
作者：
Ji, C;Amarnath, V;Marnett, LJ
我们研究了脂质过氧化的主要代谢产物4-羟基壬烯醛（HNE）诱导肿瘤细胞凋亡的机制。以剂量和时间依赖性方式用HNE诱导的聚ADP核糖聚合酶（PARP）切割和DNA片段化处理人结直肠癌（RKO）细胞。PARP裂解和DNA片段化的诱导导致caspase-2、-3、-8和-9活化。用半胱天冬酶-3抑制剂z-DEVD-feptin或广谱半胱天冬酶抑制剂z-VAD-feptin预处理细胞，可消除半胱天冬酶活化和随后的PARP裂解。高水平Bcl-2的组成性表达保护细胞免受HNE介导的凋亡。此外，Bcl-2过表达抑制细胞色素c从线粒体的释放和随后的caspase-2，-3和-9激活。这些发现表明，HNE通过涉及细胞色素c释放和半胱天冬酶激活的依赖于细胞色素的途径触发凋亡性细胞死亡。Bcl-2过表达通过抑制细胞色素c释放保护细胞免受HNE诱导的凋亡。
We investigated the mechanism by which 4-hydroxynonenal (HNE), a major aldehydic product of lipid peroxidation, induces apoptosis in tumor cells. Treatment of human colorectal carcinoma (RKO) cells with HNE-induced poly-ADP-ribose-polymerase (PARP) cleavage and DNA fragmentation in a dose- and time-dependent manner. The induction of PARP cleavage and DNA fragmentation paralleled caspase-2, -3, -8, and -9 activation. Pretreatment of cells with an inhibitor of caspase-3, z-DEVD-fmk, or a broad spectrum caspase inhibitor, z-VAD-fmk, abolished caspase activation and subsequent PARP cleavage. Constitutive expression of high levels of Bcl-2 protected cells from HNE-mediated apoptosis. In addition, Bcl-2 overexpression inhibited cytochrome c release from mitochondria and subsequent caspase-2, -3, and -9 activation. These findings demonstrate that HNE triggers apoptotic cell death through a mitochondrion-dependent pathway involving cytochrome c release and caspase activation. Bcl-2 overexpression protected cells from HNE-induced apoptosis through inhibition of cytochrome c release.