Dihydropyridine Calcium Channel Blockers Suppress the Transcription of PD-L1 by Inhibiting the Activation of STAT1.
Dihydropyridine Calcium Channel Blockers Suppress the Transcription of PD-L1 by Inhibiting the Activation of STAT1.
复制标题
二氢吡啶钙通道阻滞剂通过抑制 STAT1 的激活来抑制 PD-L1 的转录
DOI：
10.3389/fphar.2020.539261
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发表时间：
2020
影响因子：
5.6
通讯作者：
Ding L
中科院分区：
文献类型：
--
作者：
Pan X;Li R;Guo H;Zhang W;Xu X;Chen X;Ding L
程序性死亡配体 1 (PD-L1) 在各种上皮肿瘤中表达上调，在逃避免疫系统中发挥着核心作用。除了阻断PD1/PD-L1轴的单克隆抗体外，寻找能够抑制PD-L1表达的小分子化合物可能是PD1/PD-L1治疗的另一种替代策略。在这里，我们发现二氢吡啶钙通道阻滞剂剂量依赖性地降低细胞质和细胞表面中 PD-L1 的表达。乐卡地平在 24 小时内持续抑制 IFNγ 诱导的 PD-L1 转录，而 PD-L1 蛋白的半衰期并未受到显着影响。 IFNγ 引发显着的 STAT1 磷酸化，乐卡地平消除了这种磷酸化。同样，STAT1磷酸化也可以被细胞外钙螯合剂EGTA和细胞内钙螯合剂BAPTA-AM消除。此外，乐卡地平通过下调 PD-L1 增强 T 细胞的杀伤能力。综上所述，我们的研究表明钙信号是介导 PD-L1 转录的关键因素，钙的调节可作为抑制 PD-L1 的潜在策略。
Programmed death ligand 1 (PD-L1) which is upregulated in various epithelial tumors, plays a central role in the evasion of the immune system. In addition to monoclonal antibodies that blocking PD1/PD-L1 axis, finding small molecule compounds that can suppress PD-L1 expression might be another substitutable strategy for PD1/PD-L1 based therapy. Here, we found that dihydropyridine calcium channel blockers dose-dependently reduced the expression of PD-L1, both in the cytoplasm and cell surface. IFNγ induced PD-L1 transcription was consistently suppressed by Lercanidipine in 24 h, whereas, the half-life of PD-L1 protein was not significantly affected. IFNγ trigged significant STAT1 phosphorylation, which was eliminated by Lercanidipine. Similarly, STAT1 phosphorylation could also be abolished by extracellular calcium chelating agent EGTA and intracellular calcium chelator BAPTA-AM. Furthermore, Lercanidipine enhanced killing ability of T cells by down-regulating PD-L1. Taken together, our studies suggest that calcium signal is a crucial factor that mediates the transcription of PD-L1 and regulation of calcium can be used as a potential strategy for PD-L1 inhibition.
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影响因子：
10.5
作者：
Miyazaki, T;Takaoka, A;Taniguchi, T
通讯作者：
Taniguchi, T
影响因子：
30.5
作者：
Wang, Lu;Tassiulas, Ioannis;Ivashkiv, Lionel B.
通讯作者：
Ivashkiv, Lionel B.
影响因子：
--
作者：
Audrito V;Serra S;Stingi A;Orso F;Gaudino F;Bologna C;Neri F;Garaffo G;Nassini R;Baroni G;Rulli E;Massi D;Oliviero S;Piva R;Taverna D;Mandalà M;Deaglio S
通讯作者：
Deaglio S
影响因子：
64.8
作者：
LEV, S;MORENO, H;SCHLESSINGER, J
通讯作者：
SCHLESSINGER, J
DOI：
10.1073/pnas.052159099
发表时间：
2002-04-30
影响因子：
11.1
作者：
Nair, JS;DaFonseca, CJ;Zhang, JJ
通讯作者：
Zhang, JJ