Repurposing an antidandruff agent to treating cancer: zinc pyrithione inhibits tumor growth via targeting proteasome-associated deubiquitinases
Repurposing an antidandruff agent to treating cancer: zinc pyrithione inhibits tumor growth via targeting proteasome-associated deubiquitinases
复制标题
重新利用去头屑剂治疗癌症：吡啶硫酮锌通过靶向蛋白酶体相关的去泛素酶抑制肿瘤生长
DOI：
10.18632/oncotarget.14572
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发表时间：
2017-02-21
期刊：
影响因子：
--
通讯作者：
Liu, Jinbao
中科院分区：
文献类型：
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作者：
Zhao, Chong;Chen, Xin;Liu, Jinbao
泛素-蛋白酶体系统(UPS)通过选择性地降解参与细胞关键功能的蛋白质，在各种细胞过程中发挥核心作用。靶向UPS已被证实是治疗人类癌症的一种新策略，因为20S蛋白酶体催化活性的抑制剂目前正被临床用于治疗多发性骨髓瘤和其他癌症，与蛋白酶体相关的脱泛素酶活性也是抗癌药物的有效靶点。最近的研究表明，FDA批准的去头皮剂吡硫锌可能具有抗肿瘤活性，但具体的分子机制尚不清楚。在此，我们报道了吡硫锌靶向蛋白酶体相关的DUBS(USP14和UCHL5)并抑制它们的活性，导致蛋白-泛素结合物的快速积累，但不抑制20S蛋白酶体的蛋白分解活性。此外，它在体外对多种癌细胞具有细胞毒作用，对白血病患者的骨髓细胞有选择性杀伤作用，并能有效抑制肺腺癌裸鼠移植瘤的生长。这项研究已经确定了吡硫锌，一种FDA批准的具有潜在抗肿瘤活性的药物，是一种蛋白酶体DUB抑制剂。
The ubiquitin-proteasome system (UPS) plays a central role in various cellular processes through selectively degrading proteins involved in critical cellular functions. Targeting UPS has been validated as a novel strategy for treating human cancer, as inhibitors of the 20S proteasome catalytic activity are currently in clinical use for treatment of multiple myeloma and other cancers, and the deubiquitinase activity associated with the proteasome is also a valid target for anticancer agents. Recent studies suggested that zinc pyrithione, an FDA-approved antidandruff agent, may have antitumor activity, but the detailed molecular mechanisms remain unclear. Here we report that zinc pyrithione (ZnPT) targets the proteasome-associated DUBs (USP14 and UCHL5) and inhibits their activities, resulting in a rapid accumulation of protein-ubiquitin conjugates, but without inhibiting the proteolytic activities of 20S proteasomes. Furthermore, ZnPT exhibits cytotoxic effects against various cancer cell lines in vitro, selectively kills bone marrow cells from leukemia patients ex vivo, and efficiently inhibits the growth of lung adenocarcinoma cancer cell xenografts in nude mice. This study has identified zinc pyrithione, an FDA-approved pharmacological agent with potential antitumor properties as a proteasomal DUB inhibitor.