APEH Inhibition Affects Osteosarcoma Cell Viability via Downregulation of the Proteasome.
APEH Inhibition Affects Osteosarcoma Cell Viability via Downregulation of the Proteasome.
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DOI：
10.3390/ijms17101614
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发表时间：
2016-09-23
影响因子：
5.6
通讯作者：
Palmieri G
中科院分区：
文献类型：
--
作者：
Palumbo R;Gogliettino M;Cocca E;Iannitti R;Sandomenico A;Ruvo M;Balestrieri M;Rossi M;Palmieri G
蛋白酶体是一种多酶复合物，控制大多数细胞内蛋白质的半衰期，包括那些参与细胞凋亡和细胞周期进程的蛋白质。最近，蛋白酶体抑制已被证明是一种有效的抗癌策略，尽管其下调常常伴随着严重的不良副作用。我们之前报道，肽SsCEI 4对酰基肽水解酶（APEH）的抑制可以显着影响A375黑色素瘤或Caco-2腺癌细胞系中的蛋白酶体活性，从而为基于蛋白酶体功能下游调节的治疗策略提供新的思路。在这项工作中，我们研究了一组癌细胞系中 APEH 和蛋白酶体之间的功能相关性，并评估了 SsCEI 4 治疗后的细胞增殖。结果显示，SsCEI 4 通过下调 APEH-蛋白酶体系统，特异性地在骨肉瘤 U2OS 细胞中触发增殖停滞，并积累蛋白酶体的典型特征：NF-κB、p21Waf1 和多聚泛素化蛋白。我们发现 SsCEI 4 的抗增殖作用涉及衰老样生长停滞，但没有明显的细胞毒性。这些发现代表了理解 APEH 介导的蛋白酶体下调机制的重要一步，以便设计能够有效调节蛋白酶体系统的新分子以用于替代治疗策略。
The proteasome is a multienzymatic complex that controls the half-life of the majority of intracellular proteins, including those involved in apoptosis and cell-cycle progression. Recently, proteasome inhibition has been shown to be an effective anticancer strategy, although its downregulation is often accompanied by severe undesired side effects. We previously reported that the inhibition of acylpeptide hydrolase (APEH) by the peptide SsCEI 4 can significantly affect the proteasome activity in A375 melanoma or Caco-2 adenocarcinoma cell lines, thus shedding new light on therapeutic strategies based on downstream regulation of proteasome functions. In this work, we investigated the functional correlation between APEH and proteasome in a panel of cancer cell lines, and evaluated the cell proliferation upon SsCEI 4-treatments. Results revealed that SsCEI 4 triggered a proliferative arrest specifically in osteosarcoma U2OS cells via downregulation of the APEH–proteasome system, with the accumulation of the typical hallmarks of proteasome: NF-κB, p21Waf1, and polyubiquitinylated proteins. We found that the SsCEI 4 anti-proliferative effect involved a senescence-like growth arrest without noticeable cytotoxicity. These findings represent an important step toward understanding the mechanism(s) underlying the APEH-mediated downregulation of proteasome in order to design new molecules able to efficiently regulate the proteasome system for alternative therapeutic strategies.
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影响因子：
2.8
作者：
Chen D;Dou QP
通讯作者：
Dou QP
影响因子：
2.8
作者：
Field-Smith A;Morgan GJ;Davies FE
通讯作者：
Davies FE
影响因子：
9
作者：
通讯作者：
--
DOI：
10.1016/j.bbamcr.2013.02.028
发表时间：
2014-01
影响因子：
5.1
作者：
Bassermann, Florian;Eichner, Ruth;Pagano, Michele
通讯作者：
Pagano, Michele
影响因子：
5.7
作者：
Moore, Hannah E.;Davenport, Emma L.;Davies, Faith E.
通讯作者：
Davies, Faith E.