School of Pharmacy, Guangdong Food & Drug Vocational College, Guangzhou, 510520, PR China.
School of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China.
Pancreatology. 2021 Apr;21(3):630-641. doi: 10.1016/j.pan.2021.01.023. Epub 2021 Feb 12.
Pancreatic cancer (PC) is a highly fatal malignancy with few effective therapies currently available. Recent studies have shown that PD-L1 inhibitors could be potential therapeutic targets for the treatment of PC. The present study aims to investigate the effect of Shikonin on immune evasion in PC with the involvement of the PD-L1 degradation.
Initially, the expression patterns of PD-L1 and NF-κB in PC were predicted in-silico using the GEPIA database, and were subsequently validated using PC tissues. Thereafter, the correlation of NF-κB with STAT3, CSN5 and PD-L1 was examined. PC cells were treated with Shikonin, NF-κB inhibitor, STAT3 activator, and CSN5 overexpression plasmid to investigate effects on PD-L1 glycosylation and immune evasion in PC. Finally, in vivo tumor formation was induced in C57BL/6J mice, in order to verify the in vitro results.
PD-L1, NF-κB, NF-κB p65, STAT3, and CSN5 were highly expressed in PC samples, and NF-κB was positively correlated with STAT3/CSN5/PD-L1. Inhibition of NF-κB decreased PD-L1 glycosylation and increased PD-L1 degradation, whereas activated STAT3 and overexpressed CSN5 reversed these trends. Shikonin blocked immune evasion in PC, and lowered the expression of PD-L1, NF-κB, NF-κB p65, STAT3 and CSN5 in vivo and in vitro.
The findings indicated Shikonin inhibited immune evasion in PC by inhibiting PD-L1 glycosylation and activating the NF-κB/STAT3 and NF-κB/CSN5 signaling pathways. These effects of Shikonin on PC cells may bear important potential therapeutic implications for the treatment of PC.
胰腺癌（PC）是一种致命性很高的恶性肿瘤，目前可用的有效治疗方法很少。最近的研究表明，PD-L1 抑制剂可能是治疗 PC 的潜在治疗靶点。本研究旨在探讨紫草素通过 PD-L1 降解对 PC 免疫逃逸的影响。
首先，使用 GEPIA 数据库进行计算机预测，然后使用 PC 组织进行验证，以研究 PD-L1 和 NF-κB 在 PC 中的表达模式。随后，检查 NF-κB 与 STAT3、CSN5 和 PD-L1 的相关性。用紫草素、NF-κB 抑制剂、STAT3 激活剂和 CSN5 过表达质粒处理 PC 细胞，以研究它们对 PC 中 PD-L1 糖基化和免疫逃逸的影响。最后，在 C57BL/6J 小鼠中诱导体内肿瘤形成，以验证体外结果。
PD-L1、NF-κB、NF-κB p65、STAT3 和 CSN5 在 PC 样本中高表达，NF-κB 与 STAT3/CSN5/PD-L1 呈正相关。NF-κB 抑制降低了 PD-L1 的糖基化，增加了 PD-L1 的降解，而激活的 STAT3 和过表达的 CSN5 则逆转了这些趋势。紫草素阻断了 PC 中的免疫逃逸，并降低了 PD-L1、NF-κB、NF-κB p65、STAT3 和 CSN5 在体内和体外的表达。
研究结果表明，紫草素通过抑制 PD-L1 糖基化和激活 NF-κB/STAT3 和 NF-κB/CSN5 信号通路抑制 PC 中的免疫逃逸。紫草素对 PC 细胞的这些作用可能对 PC 的治疗具有重要的潜在治疗意义。
