Induction of the lysosomal apoptosis pathway by inhibitors of the ubiquitin-proteasome system
Induction of the lysosomal apoptosis pathway by inhibitors of the ubiquitin-proteasome system
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DOI：
10.1002/ijc.24004
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发表时间：
2009-03-15
影响因子：
6.4
通讯作者：
Linder, Stig
中科院分区：
文献类型：
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作者：
Berndtsson, Maria;Beaujouin, Melanie;Linder, Stig
溶酶体凋亡途径是一个潜在的治疗靶点。由于涉及溶酶体途径的细胞凋亡已被描述为涉及组织蛋白酶，我们筛选了药物库的药物诱导组织蛋白酶依赖性细胞凋亡。使用药理学抑制剂和siRNA，我们确定了2个结构相关的代理商（NSC 687852和NSC 638646），诱导组织蛋白酶D依赖性胱天蛋白酶切割活性的人乳腺癌细胞。发现这两种药物均诱导线粒体凋亡途径。发现NSC 687852和NSC 638646抑制泛素异肽酶的活性并诱导细胞中高分子量泛素的积累。我们发现，蛋白酶体降解途径的其他3种抑制剂诱导溶酶体膜透化（LMP），组织蛋白酶-D siRNA抑制这些药物诱导的细胞凋亡。我们的结论是，筛选组织蛋白酶依赖性细胞凋亡诱导剂导致鉴定泛素异肽酶抑制剂和具有不同作用机制的蛋白酶体抑制剂诱导LMP和组织蛋白酶D依赖性细胞凋亡。(C)2008 Wiley-Liss，Inc.
The lysosomal apoptosis pathway is a potentially interesting therapeutic target. Since apoptosis involving the lysosomal pathway has been described to involve cathepsins, we screened a drug library for agents that induce cathepsin-dependent apoptosis. Using pharmacological inhibitors and siRNA, we identified 2 structurally related agents (NSC687852 and NSC638646) that induced cathepsin D-dependent caspase-cleavage activity in human breast cancer cells. Both agents were found to induce the mitochondrial apoptosis pathway. NSC687852 and NSC638646 were found to inhibit the activity of ubiquitin isopeptidases and to induce the accumulation of high-molecular-mass ubiquitins in cells. We show that 3 other inhibitors of the proteasome degradation pathway induce lysosomal membrane permeabilization (LMP) and that cathepsin-D siRNA inhibits apoptosis induced by these agents. We conclude that a screen for cathepsin-dependent apoptosis-inclucing agents resulted in the identification of ubiquitin isopeptidase inhibitors and that proteasome inhibitors with different mechanisms of action induce LMP and cathepsin D-dependent apoptosis. (C) 2008 Wiley-Liss, Inc.