Apoptin-induced cell death is modulated by Bcl-2 family members and is Apaf-1dependent
Apoptin-induced cell death is modulated by Bcl-2 family members and is Apaf-1dependent
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DOI：
10.1038/sj.onc.1209258
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发表时间：
2006-04-01
期刊：
影响因子：
8
通讯作者：
Los, M
中科院分区：
文献类型：
--
作者：
Burek, M;Maddika, S;Los, M
凋亡素是鸡贫血病毒的一种蛋白质，它选择性地诱导转化细胞凋亡，而不诱导正常细胞凋亡，因此使其成为一种有前途的新型抗癌药物。其诱导细胞凋亡的机制尚不清楚。在这里，我们报告说，与以前的假设相反，Bcl-2和Bcl-x（L）抑制在几种肿瘤细胞系中的抑制素诱导的细胞死亡。与此相反，Bax的缺乏赋予耐药性，而Bax的表达致敏的细胞，抑制素诱导的死亡。细胞死亡的诱导与细胞色素c从线粒体的释放，以及与半胱天冬酶-3和-7激活。苄氧基羰基-Val-Ala-Asp-fluoromethyl ketone是一种广谱的caspase抑制剂，对阿糖胞苷诱导的细胞死亡具有高度的保护作用。由Apartin诱导的凋亡需要Apaf-1，因为永生化的Apaf-1缺陷的成纤维细胞以及缺乏Apaf-1的肿瘤细胞受到强烈保护。因此，我们的数据表明，阿邦汀诱导的细胞凋亡不仅是Bcl-2和caspase依赖性的，但也从事Apaf-1线粒体介导的线粒体死亡途径。
Apoptin, a chicken anemia virus-derived protein, selectively induces apoptosis in transformed but not in normal cells, thus making it a promising candidate as a novel anticancer therapeutic. The mechanism of apoptin-induced apoptosis is largely unknown. Here, we report that contrary to previous assumptions, Bcl-2 and Bcl-x(L) inhibit apoptin-induced cell death in several tumor cell lines. In contrast, deficiency of Bax conferred resistance, whereas Bax expression sensitized cells to apoptin-induced death. Cell death induction by apoptin was associated with cytochrome c release from mitochondria as well as with caspase-3 and -7 activation. Benzyloxy-carbonyl-Val-Ala-Asp-fluoromethyl ketone, a broad spectrum caspase inhibitor, was highly protective against apoptin-induced cell death. Apoptosis induced by apoptin required Apaf-1, as immortalized Apaf-1-deficient fibroblasts as well as tumor cells devoid of Apaf-1 were strongly protected. Thus, our data indicate that apoptin-induced apoptosis is not only Bcl-2- and caspase dependent, but also engages an Apaf-1 apoptosome-mediated mitochondrial death pathway.