Levamisole enhances DR4-independent apoptosis induced by TRAIL through inhibiting the activation of JNK in lung cancer
Levamisole enhances DR4-independent apoptosis induced by TRAIL through inhibiting the activation of JNK in lung cancer
复制标题
左旋咪唑通过抑制肺癌中 JNK 的激活增强 TRAIL 诱导的不依赖于 DR4 的细胞凋亡
DOI：
10.1016/j.lfs.2020.118034
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发表时间：
2020-09-15
期刊：
影响因子：
6.1
通讯作者：
Chen, Shu-zhen
中科院分区：
文献类型：
--
作者：
Qiao, Xinran;Wang, Chen;Chen, Shu-zhen
标题目的：左旋咪唑具有抗寄生虫和抗肿瘤活性，但其抗肺癌机制尚未研究。肿瘤坏死因子相关凋亡诱导配体（TRAIL）由于能够选择性地靶向癌细胞而被认为是一种有前途的药物。然而，癌细胞对TRAIL的耐受性限制了其抗肿瘤活性。需要探索其他与 TRAIL 联用的药物以增强其抗肿瘤活性。基于左旋咪唑对抗癌药物活性的辅助抗癌作用，考察左旋咪唑联合TRAIL的抗肿瘤活性。材料与方法：采用体外和体内实验研究其抗肿瘤活性。采用流式细胞术分析、蛋白质印迹和siRNA转染来探讨其分子机制。主要发现：左旋咪唑在体外和体内降低肺癌细胞的增殖，并诱导细胞周期停滞在G0/G1期。此外，左旋咪唑还通过抑制cJUN的磷酸化来增强TRAIL诱导的不依赖于DR4的细胞凋亡。还公开了一条新的细胞保护通路LC3B-DR4/Erk，其中左旋咪唑仅增加LC3B的表达，然后激活Erk的磷酸化并增加DR4的表达，而p-Erk和DR4相互调节。意义：左旋咪唑可能作为TRAIL的佐剂治疗肺癌。 LC3BDR4/Erk作为一种新的保护途径的发现，为肺癌细胞对TRAIL敏感提供了新的方向。
The headings aims: Levamisole has anti-parasite and antitumor activities, but the anti-lung cancer mechanism has not been studied. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is regarded as a promising drug because of the ability to selectively target cancer cells. However, the tolerance of cancer cells to TRAIL limits its antitumor activity. Other drugs combined with TRAIL need to be explored to enhance its antitumor activity. Based on the adjuvant anticancer effect of levamisole on anticancer drugs activity, the antitumor activity of levamisole combined with TRAIL will be investigated.Materials and methods: In vitro and in vivo experiments were employed to investigate the anti-tumor activity. Flow-cytometry analysis, western blotting and siRNA transfection were used to explore the molecular mechanism.Key findings: Levamisole decreased the proliferation of lung cancer cells in vitro and in vivo and induced cell cycle arrest in G0/G1 phase. Besides, levamisole also enhanced TRAIL-induced DR4-independent apoptosis by inhibiting the phosphorylation of cJUN. A new cellular protective pathway LC3B-DR4/Erk was also disclosed, in which levamisole only increased the expression of LC3B and then activated the phosphorylation of Erk and increased the expression of DR4, while p-Erk and DR4 inter-regulated.Significance: Levamisole may be used as an adjuvant of TRAIL in treating lung cancer. The discovery of LC3BDR4/Erk as a new protective pathway provides a new direction for sensitizing lung cancer cells to TRAIL.