Triggering of a novel intrinsic apoptosis pathway by the kinase inhibitor staurosporine: activation of caspase-9 in the absence of Apaf-1
Triggering of a novel intrinsic apoptosis pathway by the kinase inhibitor staurosporine: activation of caspase-9 in the absence of Apaf-1
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DOI：
10.1096/fj.10-177527
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发表时间：
2011-09-01
期刊：
影响因子：
4.8
通讯作者：
Wesselborg, Sebastian
中科院分区：
文献类型：
--
作者：
Manns, Joachim;Daubrawa, Merle;Wesselborg, Sebastian
蛋白激酶抑制剂staurosporine是最有效和最常用的促凋亡刺激之一，尽管其作用机制尚不清楚。本研究表明，星孢素及其类似物7-羟基星孢素（UCN-01）不仅能触发经典的线粒体凋亡途径，而且还能激活一种新的内在凋亡途径。与常规抗癌药物不同，staurosporine和UCN-01在多种过度表达凋亡抑制剂Bcl-2和Bcl-xL的肿瘤细胞中诱导凋亡。此外，staurosporine激活这一新的内在凋亡途径并不依赖于Apaf-1和凋亡体的形成，而Apaf-1和凋亡体是线粒体途径的必要条件。然而，正如在caspase-9缺失的小鼠胚胎成纤维细胞、人淋巴瘤细胞和鸡DT40细胞中所证明的那样，stauo孢素诱导的细胞凋亡基本上是由caspase-9介导的。因此，我们的研究结果表明，除了经典的依赖于细胞色素c/ apaf -1的caspase-9激活途径外，staurosporine可以独立于凋亡体诱导caspase-9激活和凋亡。由于staurosporine衍生物在临床试验中已被证明有效，激活这一新途径可能是诱导多药耐药肿瘤细胞凋亡的一个强有力的靶点。-Manns， J., Daubrawa， M., Driessen， S., Paasch， F., Hoffmann， N., Loffler， A., Lauber， K., Dieterle， A., Alers， S., Iftner， T., Schulze-Osthoff， K., Stork， B., Wesselborg， S.激酶抑制剂staurosporine触发一种新的内在凋亡途径：在Apaf-1缺失的情况下激活caspase-9。中华医学杂志，25（2011）。www.fasebj.org
The protein kinase inhibitor staurosporine is one of the most potent and frequently used proapoptotic stimuli, although its mechanism of action is poorly understood. Here, we show that staurosporine as well as its analog 7-hydroxystaurosporine (UCN-01) not only trigger the classical mitochondrial apoptosis pathway but, moreover, activate an additional novel intrinsic apoptosis pathway. Unlike conventional anticancer drugs, staurosporine and UCN-01 induced apoptosis in a variety of tumor cells overexpressing the apoptosis inhibitors Bcl-2 and Bcl-xL. Furthermore, activation of this novel intrinsic apoptosis pathway by staurosporine did not rely on Apaf-1 and apoptosome formation, an essential requirement for the mitochondrial pathway. Nevertheless, as demonstrated in caspase-9-deficient murine embryonic fibroblasts, human lymphoma cells, and chicken DT40 cells, stauro-sporine-induced apoptosis was essentially mediated by caspase-9. Our results therefore suggest that, in addition to the classical cytochrome c/Apaf-1-dependent pathway of caspase-9 activation, staurosporine can induce caspase-9 activation and apoptosis independently of the apoptosome. Since staurosporine derivatives have proven efficacy in clinical trials, activation of this novel pathway might represent a powerful target to induce apoptosis in multidrug-resistant tumor cells.-Manns, J., Daubrawa, M., Driessen, S., Paasch, F., Hoffmann, N., Loffler, A., Lauber, K., Dieterle, A., Alers, S., Iftner, T., Schulze-Osthoff, K., Stork, B., Wesselborg, S. Triggering of a novel intrinsic apoptosis pathway by the kinase inhibitor staurosporine: activation of caspase-9 in the absence of Apaf-1. FASEB J. 25, 3250-3261 (2011). www.fasebj.org