Berberine diminishes cancer cell PD-L1 expression and facilitates antitumor immunity via inhibiting the deubiquitination activity of CSN5.
Berberine diminishes cancer cell PD-L1 expression and facilitates antitumor immunity via inhibiting the deubiquitination activity of CSN5.
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小檗碱通过抑制 CSN5 的去泛素化活性减少癌细胞 PD-L1 表达并促进抗肿瘤免疫
DOI：
10.1016/j.apsb.2020.06.014
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发表时间：
2020-12
期刊：
影响因子：
--
通讯作者：
Deng H
中科院分区：
文献类型：
--
作者：
Liu Y;Liu X;Zhang N;Yin M;Dong J;Zeng Q;Mao G;Song D;Liu L;Deng H
程序性细胞死亡-1(PD-1)/程序性细胞死亡配体-1(PD-L1)阻断治疗已成为肿瘤免疫治疗的主要支柱。与抗体靶向相比，迫切需要具有良好药代动力学的小分子检查点抑制剂。在这里，我们从一系列中药化学单体中鉴定出黄连素(BBR)是一种已被证实的抗炎药物，是PD-L1的负调节因子。BBR通过降低肿瘤细胞中PD-L1的水平，提高肿瘤细胞对共培养T细胞的敏感性。此外，BBR还通过增强肿瘤浸润性T细胞免疫，减弱免疫抑制的髓系来源抑制细胞(MDSCs)和调节性T细胞(Tregs)的激活，发挥其对Lewis肿瘤移植瘤小鼠的抗肿瘤作用。BBR通过泛素(Ub)/蛋白酶体依赖途径启动PD-L1降解。值得注意的是，BBR选择性地与构成光形态发生-9信号小体5(CSN5)的谷氨酸76结合，并通过其去泛素化活性抑制PD-1/PD-L1轴，导致PD-L1的泛素化和降解。我们的数据揭示了BBR以前未知的抗肿瘤机制，表明BBR是用于癌症治疗的小分子免疫检查点抑制剂。黄连素通过抑制COP9信号体5(CSN5)的去泛素化活性，减少非小细胞肺癌细胞程序性死亡配体-1的表达，促进抗肿瘤免疫。
Programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) blocking therapy has become a major pillar of cancer immunotherapy. Compared with antibodies targeting, small-molecule checkpoint inhibitors which have favorable pharmacokinetics are urgently needed. Here we identified berberine (BBR), a proven anti-inflammation drug, as a negative regulator of PD-L1 from a set of traditional Chinese medicine (TCM) chemical monomers. BBR enhanced the sensitivity of tumour cells to co-cultured T-cells by decreasing the level of PD-L1 in cancer cells. In addition, BBR exerted its antitumor effect in Lewis tumor xenograft mice through enhancing tumor-infiltrating T-cell immunity and attenuating the activation of immunosuppressive myeloid-derived suppressor cells (MDSCs) and regulatory T-cells (Tregs). BBR triggered PD-L1 degradation through ubiquitin (Ub)/proteasome-dependent pathway. Remarkably, BBR selectively bound to the glutamic acid 76 of constitutive photomorphogenic-9 signalosome 5 (CSN5) and inhibited PD-1/PD-L1 axis through its deubiquitination activity, resulting in ubiquitination and degradation of PD-L1. Our data reveals a previously unrecognized antitumor mechanism of BBR, suggesting BBR is small-molecule immune checkpoint inhibitor for cancer treatment. Berberine diminishes the expression of programmed cell death ligand-1 and promotes antitumor immunity via inhibiting the deubiquitination activity of COP9 signalosome 5 (CSN5) in non-small cell lung cancer.
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影响因子：
3.7
作者：
Liu B;Wang G;Yang J;Pan X;Yang Z;Zang L
通讯作者：
Zang L
DOI：
10.6004/jnccn.2013.0084
发表时间：
2013-06-01
影响因子：
13.4
作者：
Ettinger, David S.;Akerley, Wallace;Hughes, Miranda
通讯作者：
Hughes, Miranda
影响因子：
50.3
作者：
Lim SO;Li CW;Xia W;Cha JH;Chan LC;Wu Y;Chang SS;Lin WC;Hsu JM;Hsu YH;Kim T;Chang WC;Hsu JL;Yamaguchi H;Ding Q;Wang Y;Yang Y;Chen CH;Sahin AA;Yu D;Hortobagyi GN;Hung MC
通讯作者：
Hung MC
PD-1检查点途径的分子和生化方面。
DOI：
10.1056/nejmra1514296
发表时间：
2016-11-03
期刊：
The New England journal of medicine
影响因子：
--
作者：
Boussiotis VA
通讯作者：
Boussiotis VA
影响因子：
64.8
作者：
Burr ML;Sparbier CE;Chan YC;Williamson JC;Woods K;Beavis PA;Lam EYN;Henderson MA;Bell CC;Stolzenburg S;Gilan O;Bloor S;Noori T;Morgens DW;Bassik MC;Neeson PJ;Behren A;Darcy PK;Dawson SJ;Voskoboinik I;Trapani JA;Cebon J;Lehner PJ;Dawson MA
通讯作者：
Dawson MA