SA-49, a novel aloperine derivative, induces MITF-dependent lysosomal degradation of PD-L1
SA-49, a novel aloperine derivative, induces MITF-dependent lysosomal degradation of PD-L1
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SA-49 是一种新型苦豆碱衍生物，可诱导 PD-L1 的 MITF 依赖性溶酶体降解
DOI：
10.1016/j.ebiom.2019.01.054
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发表时间：
2019-01
期刊：
影响因子：
11.1
通讯作者：
Danqing Song
中科院分区：
文献类型：
--
作者：
Na Zhang;Yueying Dou;Lu Liu;Xin Zhang;Xiaojia Liu;Qingxuan Zeng;Yang Liu;Minxiao Yin;Xiujun Liu;Hongbin Deng;Danqing Song
程序性死亡配体1(PD-L1)是一种抑制抗肿瘤免疫的T细胞抑制性检查点分子。抗PD-L1抗体在治疗肿瘤方面显示出显著的前景，但患者的应答率很低。因此，迫切需要阻断PD-L1功能的小分子检查点抑制剂。方法用免疫印迹法检测PD-L1蛋白表达和磷酸化水平的变化。用流式细胞仪检测细胞膜PD-L1水平。用乳酸脱氢酶和细胞指数法检测T细胞和NK细胞对肿瘤细胞的杀伤活性。NAG法检测溶酶体功能。RT-PCR检测溶酶体相关基因的变化。通过荷Lewis瘤的C57BL/6小鼠体内抗NSCLC实验，我们从一系列新的苦杏仁碱衍生物中鉴定出SA-49是一种新的PD-L1表达调节因子。SA-49可降低NSCLC细胞中PD-L1的表达，增强共培养的T细胞和NK细胞对肿瘤细胞的杀伤作用。重要的是，溶酶体途径参与了SA-49介导的PD-L1的下调。SA-49促进溶酶体的生物合成，促进PD-L1转位到溶酶体进行蛋白分解，这与MITF的核转位有关。SA-49诱导的MITF易位是通过激活PKCα，进而抑制GSK3β活性起作用的。此外，SA-49通过激活免疫微环境抑制Lewis肿瘤在C57BL/6小鼠体内的生长。
BackgroundProgrammed death-ligand 1 (PD-L1) is a T-cell inhibitory checkpoint molecule that suppresses antitumor immunity. Anti-PD-L1 antibodies have shown remarkable promise in treating tumors, but the patient response rate is low. Therefore, small-molecule checkpoint inhibitors blocking PD-L1 function are urgently needed.MethodsChanges of protein expression and phosphorylation levels were determined by immunoblotting. The level of Membrane PD-L1 was examined by flow cytometer. Cytotoxicity of T cells and NK cells toward tumor cells were detected using LDH and cell index assays. Lysosome function was investigated by NAG assay. Changes in lysosomal-related genes were measured by RT-PCR. In vivo anti-NSCLC cancer effects were assessed using C57BL/6 mice bearing Lewis tumor xenografts.FindingsWe identified SA-49 as a new regulator of PD-L1 expression from a series of novel aloperine derivatives. SA-49 decreased the expression of PD-L1 in NSCLC cells and enhanced the cytotoxicity of co-cultured T and NK cells toward tumor cells. Importantly, lysosomal pathway contributed to SA-49-mediated down-regulation of PD-L1. SA-49 increased the biogenesis of lysosome and promoted translocation of PD-L1 to lysosome for proteolysis, which was associated with nuclear translocation of MITF. SA-49-induced MITF translocation acted through activation of PKCα and subsequently suppression of GSK3β activity. Furthermore, SA-49 suppressed Lewis tumor xenograft growth by activating immune microenvironment in C57BL/6 mice.InterpretationOur data demonstrate that SA-49 can be used to regulate PD-L1 in cancer cells and trigger its degradation by activating lysosome function.
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影响因子：
18.2
作者：
Xu H;Ren D
通讯作者：
Ren D
DOI：
10.1146/annurev-cellbio-111315-125125
发表时间：
2016-10-06
影响因子：
11.3
作者：
Perera RM;Zoncu R
通讯作者：
Zoncu R
Aloperine 通过双重细胞凋亡机制对多发性骨髓瘤发挥抗肿瘤作用。
影响因子：
28.5
作者：
Wang H;Yang S;Zhou H;Sun M;Du L;Wei M;Luo M;Huang J;Deng H;Feng Y;Huang J;Zhou Y
通讯作者：
Zhou Y
DOI：
10.1038/nrm3565
发表时间：
2013-05
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
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影响因子：
7.5
作者：
Chen, Shao;Jin, Zhicheng;Gao, Weiyang
通讯作者：
Gao, Weiyang