Cathepsin X promotes 6-hydroxydopamine-induced apoptosis of PC12 and SH-SY5Y cells
Cathepsin X promotes 6-hydroxydopamine-induced apoptosis of PC12 and SH-SY5Y cells
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DOI：
10.1016/j.neuropharm.2013.07.040
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发表时间：
2014-07-01
影响因子：
4.7
通讯作者：
Kos, Janko
中科院分区：
文献类型：
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作者：
Pislar, Anja Hafner;Zidar, Nace;Kos, Janko
半胱氨酸羧肽酶组织蛋白酶X在正常衰老和病理条件下的退行性过程中起重要作用。在本研究中，我们研究了组织蛋白酶X在6-羟基多巴胺（6-OHDA）诱导嗜铬细胞瘤细胞系PC12和神经母细胞瘤细胞系SH-SY5Y毒性中的潜在作用。暴露于6-OHDA的细胞表现出组织蛋白酶X蛋白水平和组织蛋白酶X活性的改变。通过siRNA下调组织蛋白酶X表达可减轻6-OHDA引起的神经元死亡。用特异性组织蛋白酶X抑制剂AMS36处理可保护细胞免受6-OHDA介导的细胞毒性，减少细胞死亡和凋亡。此外，AMS36逆转了6- ohda诱导的酪氨酸羟化酶的丧失，减弱了6- ohda诱导的caspase-3的激活，引发细胞凋亡、细胞内活性氧的产生和线粒体功能障碍，包括细胞色素c的释放和Bax/Bcl-2比例失衡。此外，AMS36通过阻断I κ B α的降解来干扰NF-kappa B的激活，阻止NF-kappa B转运到细胞核。我们的数据提供了第一个证据，表明抑制组织蛋白酶X可以保护PC12和SH-SY5Y细胞免受6-OHDA的毒性，并表明组织蛋白酶X可能负责多巴胺神经元死亡，参与神经退行性疾病（如帕金森病）的致病性级联事件。(C) 2013 Elsevier Ltd.版权所有。
The cysteine carboxypeptidase cathepsin X is an important player in degenerative processes under normal ageing and pathological conditions. In the present study, we investigated the potential role of cathepsin X in 6-hydroxydopamine (6-OHDA)-induced toxicity in the pheochromocytoma cell line PC12 and neuroblastoma cell line SH-SY5Y. Cells exposed to 6-OHDA demonstrated alterations in the protein level of cathepsin X and activity of cathepsin X. Downregulation of cathepsin X expression by siRNA attenuated the neuronal death caused by 6-OHDA. Treatment with specific cathepsin X inhibitor AMS36 protected cells against 6-OHDA mediated cytotoxicity, resulting in reduced cell death and apoptosis. Furthermore, AMS36 reversed 6-OHDA-induced loss of tyrosine hydroxylase and attenuated 6-OHDA-induced activation of caspase-3, triggering apoptosis, intracellular generation of reactive oxygen species and mitochondrial dysfunction, including the release of cytochrome c and an imbalanced Bax/Bcl-2 ratio. Moreover, AMS36 interfered with NF-kappa B activation by blocking degradation of I kappa B alpha, preventing NF-kappa B translocation to the nucleus. Our data provide the first evidence that inhibition of cathepsin X protects both, PC12 and SH-SY5Y cells against 6-OHDA toxicity and indicate that cathepsin X may be responsible for dopamine neuron death, involved in the pathogenic cascade event for the neurodegenerative disorders, such as Parkinson's disease. (C) 2013 Elsevier Ltd. All rights reserved.