The polyamines regulate endothelial cell survival during hypoxic stress through PI3K/AKT and MCL-1
The polyamines regulate endothelial cell survival during hypoxic stress through PI3K/AKT and MCL-1
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DOI：
10.1016/j.bbrc.2009.01.097
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发表时间：
2009-03-06
影响因子：
3.1
通讯作者：
Belting, Mattias
中科院分区：
文献类型：
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作者：
Kucharzewska, Paulina;Welch, Johanna E.;Belting, Mattias
缺氧依赖性血管生成是实体瘤的固有特征，更好地理解缺氧细胞死亡的分子机制将为癌症治疗提供额外的靶点。在这里，我们显示了一种新的作用，多胺在内皮细胞（EC）的生存在缺氧。通过特异性抑制鸟氨酸脱羧酶的多胺消耗被证明可以保护内皮细胞免受缺氧诱导的凋亡。多胺的抑制导致PI 3 K/AKT及其下游靶标MCL-1（即BCL-2家族的抗凋亡成员）的显著诱导。PI 3 K的特异性抑制剂逆转缺氧诱导的细胞凋亡的减少以及多胺剥夺细胞中MCL-1的诱导。此外，发现siRNA介导的MCL-1的下调抵消了多胺抑制的保护作用。结论：多胺通过PI 3 K/AKT和MCL-1依赖性途径调节缺氧诱导的内皮细胞凋亡。我们的研究结果可能对低氧驱动的新生血管的调节具有重要意义。(C)2009 Elsevier Inc.版权所有
Hypoxia-dependent angiogenesis is an inherent feature of solid tumors, and a better understanding of the molecular mechanisms of hypoxic cell-death should provide additional targets for cancer therapy. Here, we show a novel role of the polyamines in endothelial cell (EC) survival during hypoxia. Polyamine depletion by specific inhibition of ornithine decarboxylase was shown to protect ECs from hypoxia-induced apoptosis. Inhibition of the polyamines resulted in a significant induction of PI3K/AKT and its downstream target MCL-1, i.e. an anti-apoptotic member of the BCL-2 family. Specific inhibitors of PI3K reversed the decrease of hypoxia-induced apoptosis as well as the induction of MCL-1 in polyaminedeprived cells. Moreover, siRNA-mediated down-regulation of MCL-1 was found to counter-act the protective effect of polyamine inhibition. We conclude that the polyamines regulate hypoxia-induced apoptosis in ECs through PI3K/AKT and MCL-1 dependent pathways. Our results may have important implications for the modulation of hypoxia-driven neovascularization. (C) 2009 Elsevier Inc. All rights reserved