Direct interaction between caffeic acid phenethyl ester and human neutrophil elastase inhibits the growth and migration of PANC-1 cells
Direct interaction between caffeic acid phenethyl ester and human neutrophil elastase inhibits the growth and migration of PANC-1 cells
复制标题
咖啡酸苯乙酯与人中性粒细胞弹性蛋白酶之间的直接相互作用抑制 PANC-1 细胞的生长和迁移。
DOI：
10.3892/or.2017.5516
复制
发表时间：
2017-05-01
期刊：
影响因子：
4.2
通讯作者：
Li, Xuejun
中科院分区：
文献类型：
--
作者：
Duan, Jianhui;Xiaokaiti, Yilixiati;Li, Xuejun
胰腺导管腺癌（PDAC）是消化系统最致命的恶性肿瘤之一，但其发生发展的机制尚不清楚。炎症被认为是胰腺癌发展的基础，咖啡酸苯乙酯（CAPE）是蜜蜂树脂或蜂胶的活性成分，具有抗炎和抗癌活性。我们研究了CAPE对人中性粒细胞弹性蛋白酶（HNE）诱导的细胞生长和迁移的抑制作用，并报告HNE在低剂量下诱导癌细胞迁移，在高剂量下诱导癌细胞生长。相比之下，较低剂量的CAPE抑制迁移，较高剂量的CAPE抑制HNE诱导的生长。CAPE（7.5-120 µM）显著抑制HNE活性。使用定量实时PCR和蛋白质印迹法，我们观察到CAPE（18-60 µM）不影响内源性HNE抑制剂α1-抗胰蛋白酶（α1-AT）的转录和翻译。然而，在计算机药物靶点对接模型中，我们发现CAPE直接结合到HNE的结合口袋（25.66 kcal/mol）根据CDOCKER，和催化位点的残基稳定CAPE和HNE之间的相互作用，证明了分子动力学模拟。表面等离子体共振（SPR）的响应单位（RU）值随着CAPE剂量的增加（7.5-120 µM）而显著增加，表明CAPE可以以浓度依赖性方式直接结合HNE。因此，CAPE是通过直接相互作用的HNE的有效抑制剂，由此其以剂量依赖性方式抑制PANC-1细胞的迁移和生长。
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignant tumors of the digestive system, but the mechanisms of its development and progression are unclear. Inflammation is thought to be fundamental to pancreatic cancer development and caffeic acid phenethyl ester (CAPE) is an active component of honey bee resin or propolis with anti-inflammatory and anticancer activities. We investigated the inhibitory effects of CAPE on cell growth and migration induced by human neutrophil elastase (HNE) and report that HNE induced cancer cell migration at low doses and growth at higher doses. In contrast, lower CAPE doses inhibited migration and higher doses of CAPE inhibited the growth induced by HNE. HNE activity was significantly inhibited by CAPE (7.5-120 µM). Using quantitative real-time PCR and western blotting, we observed that CAPE (18-60 µM) did not affect transcription and translation of α1-antitrypsin (α1-AT), an endogenous HNE inhibitor. However, in an in silico drug target docking model, we found that CAPE directly bound to the binding pocket of HNE (25.66 kcal/mol) according to CDOCKER, and the residue of the catalytic site stabilized the interaction between CAPE and HNE as evidenced by molecular dynamic simulation. Response unit (RU) values of surface plasmon resonance (SPR) significantly increased with incremental CAPE doses (7.5-120 µM), indicating that CAPE could directly bind to HNE in a concentration-dependent manner. Thus, CAPE is an effective inhibitor of HNE via direct interaction whereby it inhibits the migration and growth of PANC-1 cells in a dose-dependent manner.