Henderson C J, Aleo E, Fontanini A, Maestro R, Paroni G, Brancolini C
MATI Center of Excellence, Universita' di Udine. P.le Kolbe 4, Udine 33100, Italy.
Cell Death Differ. 2005 Sep;12(9):1240-54. doi: 10.1038/sj.cdd.4401729.
Several studies have indicated that proteasome inhibitors (PIs) are promising anticancer agents. We have discovered that PIs have the unique ability to activate effector caspases through a mitochondrial Bcl-2 inhibitable but caspase-9 independent pathway. Stabilization of released Smac induced by blockade of the proteasome could explain the apoptosome-independent cell death induced by PIs. In fact, Smac/DIABLO critically supports this PIs-dependent caspase activation. By using a new assay, we confirm that at a single cell level both Smac and PIs can activate caspases in the absence of the apoptosome. Moreover, we have observed two PIs-induced kinetics of caspase activation, with caspase-9 being still required for the rapid caspase activation in response to mitochondrial depolarization, but dispensable for the slow DEVDase activation. In summary, our data indicate that PIs can activate downstream caspases at least in part through Smac/DIABLO stabilization.
多项研究表明，蛋白酶体抑制剂（PIs）是很有前景的抗癌药物。我们发现，PIs具有通过线粒体Bcl-2可抑制但caspase-9非依赖途径激活效应caspases的独特能力。蛋白酶体阻断诱导释放的Smac的稳定化可以解释PIs诱导的不依赖凋亡小体的细胞死亡。事实上，Smac/DIABLO对这种PIs依赖的caspase激活起着关键支持作用。通过使用一种新的检测方法，我们证实，在单细胞水平上，Smac和PIs在没有凋亡小体的情况下都能激活caspases。此外，我们观察到两种PIs诱导的caspase激活动力学，其中caspase-9对于响应线粒体去极化的快速caspase激活仍然是必需的，但对于缓慢的DEVDase激活则是可有可无的。总之，我们的数据表明，PIs至少部分可以通过Smac/DIABLO的稳定化来激活下游caspases。
