Apoptosis-resistance of hypoxic cells - Multiple factors involved and a role for IAP-2
Apoptosis-resistance of hypoxic cells - Multiple factors involved and a role for IAP-2
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DOI：
10.1016/s0002-9440(10)63693-0
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发表时间：
2003-08-01
影响因子：
6
通讯作者：
Venkatachalam, MA
中科院分区：
文献类型：
--
作者：
Dong, Z;Wang, JZ;Venkatachalam, MA
缺氧是缺血性疾病和肿瘤发生的重要致病因素。在缺氧的情况下，一些细胞会受到不可逆的损伤，而另一些细胞则会适应压力，并可能对损伤更具抵抗力。这种适应性反应的机制尚不清楚。我们最近的研究表明，缺氧诱导凋亡抑制蛋白-2（IAP-2）。在这里，我们研究了受缺氧影响的凋亡级联反应中的关键步骤，并确定了IAP-2在缺氧细胞抗凋亡中的作用。结果表明，在缺氧条件下培养的细胞变得对星形孢菌素诱导的细胞凋亡具有抗性。这些细胞的凋亡抗性发生在线粒体和胞浆中。在线粒体水平上，促凋亡分子Bax的膜积累受到抑制。这是伴随着较少的细胞色素c（cyt。c）从细胞器中释放。在细胞质中，缺氧诱导IAP-2，IAP-2的细胞质对cyt具有抗性。c-刺激的半胱天冬酶活化。重要的是，免疫耗竭IAP-2从缺氧的细胞质恢复其能力的半胱天冬酶激活。因此，缺氧细胞的死亡抗性涉及靶向细胞凋亡的不同阶段的多种因素，其中IAP-2抑制胞质溶胶中的半胱天冬酶。
Hypoxia is an important pathogenic factor in ischemic disease and tumorigenesis. Under hypoxia, some cells are irreversibly damaged, whereas others adapt to the stress and may become more resistant to injury. The mechanism underlying such adaptive responses is unclear. Our recent study showed hypoxic induction of inhibitor of apoptosis protein-2 (IAP-2). Here we have investigated the critical steps in the apoptotic cascade that are affected by hypoxia and have identified a role for IAP-2 in apoptosis resistance of hypoxic cells. The results show that cells cultured in hypoxia became resistant to staurosporine-induced apoptosis. Apoptosis resistance of these cells took place at the mitochondria and in the cytosol. At the mitochondrial level, membrane accumulation of the proapoptotic molecule Bax was suppressed. This was accompanied by less cytochrome c (cyt. c) release from the organelles. In the cytosol, hypoxia induced IAP-2; the cytosol with IAP-2 was resistant to cyt. c-stimulated caspase activation. Of significance, immunodepletion of IAP-2 from the hypoxic cytosol restored its competence for caspase activation. Thus, death resistance of hypoxic cells involves multiple factors targeting different stages of apoptosis, with IAP-2 suppressing caspases in the cytosol.