Synergistic inhibition of autophagy and neddylation pathways as a novel therapeutic approach for targeting liver cancer.
Synergistic inhibition of autophagy and neddylation pathways as a novel therapeutic approach for targeting liver cancer.
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自噬和neddylation途径的协同抑制作为靶向肝癌的新型治疗方法
DOI：
10.18632/oncotarget.3282
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发表时间：
2015-04-20
期刊：
影响因子：
--
通讯作者：
Jia L
中科院分区：
文献类型：
--
作者：
Chen P;Hu T;Liang Y;Jiang Y;Pan Y;Li C;Zhang P;Wei D;Li P;Jeong LS;Chu Y;Qi H;Yang M;Hoffman RM;Dong Z;Jia L
肝癌是世界上第二大最常见的癌症死亡原因，并且具有高度的治疗抗性。我们先前报道了用特异性NAE抑制剂MLN 4924抑制neddylation途径，抑制肝癌的恶性表型。然而，在此过程中，MLN4924诱导促生存自噬作为耐药性机制。在此，我们报告了使用临床可用的自噬抑制剂（例如氯喹）阻断自噬可通过触发细胞凋亡显著增强MLN 4924对肝癌细胞的疗效。在机制上，氯喹增强了MLN 4924诱导的促凋亡蛋白（例如NOXA）上调和抗凋亡蛋白下调。重要的是，通过siRNA沉默下调NOXA表达显著减弱了肝癌细胞的凋亡。进一步的机制研究表明，自噬的阻断增加了MLN 4924诱导的DNA损伤和活性氧（ROS）的产生。DNA损伤的消除或ROS产生的阻断显著降低了NOXA的表达，从而减弱了肝癌细胞的凋亡和生长抑制。此外，阻断自噬可增强MLN 4924在人肝癌原位模型中的疗效，并诱导肿瘤组织中的NOXA和细胞凋亡。这些发现为临床研究肝癌中neddylation和自噬的协同抑制提供了重要的临床前证据。
Liver cancer is the second-most frequent cause of cancer death in the world and is highly treatment resistant. We reported previously that inhibition of neddylation pathway with specific NAE inhibitor MLN4924, suppressed the malignant phenotypes of liver cancer. However, during the process, MLN4924 induces pro-survival autophagy as a mechanism of drug resistance. Here, we report that blockage of autophagy with clinically-available autophagy inhibitors (e.g. chloroquine) significantly enhanced the efficacy of MLN4924 on liver cancer cells by triggering apoptosis. Mechanistically, chloroquine enhanced MLN4924-induced up-regulation of pro-apoptotic proteins (e.g. NOXA) and down-regulation of anti-apoptotic proteins. Importantly, the down-regulation of NOXA expression via siRNA silencing substantially attenuated apoptosis of liver cancer cells. Further mechanistic studies revealed that blockage of autophagy augmented MLN4924-induced DNA damage and reactive oxygen species (ROS) generation. The elimination of DNA damage or blockage of ROS production significantly reduced the expression of NOXA, and thereby attenuated apoptosis and reduced growth inhibition of liver cancer cells. Moreover, blockage of autophagy enhanced the efficacy of MLN4924 in an orthotopic model of human liver cancer, with induction of NOXA and apoptosis in tumor tissues. These findings provide important preclinical evidence for clinical investigation of synergistic inhibition of neddylation and autophagy in liver cancer.
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影响因子：
3.9
作者：
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通讯作者：
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作者：
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作者：
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影响因子：
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作者：
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影响因子：
11.2
作者：
Luo, Zhongguang;Yu, Guangyang;Jia, Lijun
通讯作者：
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