Autophagy Induced by Proteasomal DUB Inhibitor NiPT Restricts NiPT-Mediated Cancer Cell Death
Autophagy Induced by Proteasomal DUB Inhibitor NiPT Restricts NiPT-Mediated Cancer Cell Death
复制标题
蛋白酶体 DUB 抑制剂 NiPT 诱导的自噬限制 NiPT 介导的癌细胞死亡
DOI：
10.3389/fonc.2020.00348
复制
发表时间：
2020-03-27
影响因子：
4.7
通讯作者：
Liu, Jinbao
中科院分区：
文献类型：
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作者：
Chen, Jinghong;Chen, Xin;Liu, Jinbao
泛素-蛋白酶体系统（UPS）和自噬-溶酶体途径（ALP）是真核细胞蛋白质量控制（PQC）的两个主要系统。这两种途径之间的相互联系已经被提出，但它们如何相互影响的分子细节仍然难以捉摸。蛋白酶体去泛素酶（DUB）是UPS的重要组成部分，已被证明是一种新的抗癌靶点。我们之前已经发现一种新的DUB抑制剂，镍复合物NiPT，在培养的肿瘤细胞系和急性髓性白血病患者的癌细胞中诱导细胞凋亡。在本研究中，我们发现NiPT在体外和体内都能触发自噬。从机制上讲，NiPT靶向两种DUBs， USP14和UCHL5，并增加了细胞多泛素化的总水平。多泛素结合所需的P62泛素相关（Ubiquitin Associated， UBA）结构域的缺失阻止了npt诱导的自噬。npt诱导的自噬是通过amp激活的蛋白激酶（AMPK）的同时激活和雷帕霉素（mTOR）信号的机制靶点的抑制，或通过激活转录因子4 （ATF4）和C/ ebp同源蛋白（CHOP）引发内质网（ER）应激。此外，如果NiPT协同使用自噬抑制剂，则可以诱导更多的肺癌细胞发生凋亡，这表明NiPT诱导的自噬可以保护癌细胞免于死亡。总之，我们的研究结果表明，自噬抑制增强了蛋白酶体DUB抑制剂的抗癌作用，可能是一种有效的肺癌治疗策略。
Ubiquitin-proteasome system (UPS) and autophagy-lysosome pathway (ALP) are two major systems for protein quality control (PQC) in eukaryotic cells. Interconnectivity between these two pathways has been suggested, but the molecular detail of how they impact each other remains elusive. Proteasomal deubiquitinase (DUB) is an important constituent in the UPS and has proved to be a novel anticancer target. We have previously found that a novel DUB inhibitor, nickel complex NiPT, induces apoptosis in both cultured tumor cell lines and cancer cells from acute myeloid leukemia human patients. In this study, we found that NiPT triggered autophagy both in vitro and in vivo. Mechanistically, NiPT targets two DUBs, USP14, and UCHL5, and increased the total cellular level of polyubiquitination. Deletion of the Ubiquitin Associated (UBA) domain of P62 that is required for polyubiquitin binding prevented NiPT-induced autophagy. NiPT-induced autophagy is through either concomitant activation of AMP-activated protein kinase (AMPK) and inhibition of mechanistic target of rapamycin (mTOR) signaling, or eliciting endoplasmic reticulum (ER)-stress by activating activating transcription factor 4 (ATF4) and C/EBP-homologous protein (CHOP). Moreover, NiPT could induce more lung cancer cells undergoing apoptosis if it synergistically uses autophagy inhibitors, suggesting that NiPT-induced autophagy protects cancer cell from death. Collectively, our findings demonstrate that autophagy inhibition enhances the anticancer effects of proteasomal DUB inhibitor and might be an effective treatment strategy for lung cancer.