Cathepsin B mediates caspase-independent cell death induced by microtubule stabilizing agents in non-small cell lung cancer cells
Cathepsin B mediates caspase-independent cell death induced by microtubule stabilizing agents in non-small cell lung cancer cells
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DOI：
10.1158/0008-5472.can-03-3060
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发表时间：
2004-01-01
期刊：
影响因子：
11.2
通讯作者：
Giaccone, G
中科院分区：
文献类型：
--
作者：
Bröker, LE;Huisman, C;Giaccone, G
我们先前曾报道，微管稳定剂（MSAs）紫杉醇、埃博霉素B和盘皮海绵内酯在非小细胞肺癌（NSCLC）细胞中诱导不依赖半胱天冬酶的细胞死亡。在此我们提供两方面的证据，表明溶酶体蛋白酶组织蛋白酶B在介导细胞死亡中起核心作用。首先，抑制组织蛋白酶B，而非半胱天冬酶或其他蛋白酶，如组织蛋白酶D或钙蛋白酶，可在几种NSCLC细胞中对药物诱导的细胞死亡产生强大的保护作用。其次，MSAs引发溶酶体破裂以及组织蛋白酶B的释放和活化。有趣的是，抑制组织蛋白酶B可阻止多核细胞的出现，这是MSA诱导的细胞死亡的一个早期特征，表明组织蛋白酶B在这种新的细胞死亡途径中起核心的近端作用。
We have previously reported that the microtubule stabilizing agents (MSAs) paclitaxel, epothilone B and discodermolide induce caspase-independent cell death in non-small cell lung cancer (NSCLC) cells. Here we present two lines of evidence indicating a central role for the lysosomal protease cathepsin B in mediating cell death. First, inhibition of cathepsin B, and not of caspases or other proteases, such as cathepsin D or calpains, results in a strong protection against drug-induced cell death in several NSCLC cells. Second, MSAs trigger disruption of lysosomes and release and activation of cathepsin B. Interestingly, inhibition of cathepsin B prevents the appearance of multinucleated cells, an early characteristic of MSA-induced cell death, pointing to a central, proximal role for cathepsin B in this novel cell death pathway.