Trastuzumab Inhibits Growth of HER2-Negative Gastric Cancer Cells Through Gastrin-Initialized CCKBR Signaling
Trastuzumab Inhibits Growth of HER2-Negative Gastric Cancer Cells Through Gastrin-Initialized CCKBR Signaling
复制标题
曲妥珠单抗通过胃泌素启动的 CCKBR 信号抑制 HER2 阴性胃癌细胞的生长
DOI：
10.1007/s10620-015-3793-7
复制
发表时间：
2015-12-01
影响因子：
3.1
通讯作者：
Fu, Guo-Hui
中科院分区：
文献类型：
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作者：
Cui, Yan;Li, Shao-Bo;Fu, Guo-Hui
背景曲妥珠单抗是一种靶向人表皮生长因子受体2（HER 2，p185）的完全人源化单克隆抗体，其应用改善了HER 2阳性胃癌（GC）患者的预后，但一些相关问题仍有待研究，并将随着新的抗GC药物的出现而出现。胃泌素是一种主要的胃肠道激素，在体外和体内被证明对GC具有抑制作用。目的探讨曲妥珠单抗和胃泌素对GC的抑制作用。结果我们发现曲妥珠单抗和胃泌素通过胃泌素/胆囊收缩素B受体（CCKBR）途径协同抑制HER 2阴性胃癌细胞。曲妥珠单抗上调CCKBR蛋白水平，但不能启动其信号转导，而胃泌素增加CCKBR的水平和激活。分子实验表明，曲妥珠单抗和胃泌素联合治疗协同增强CCKBR的稳定性。此外，它们的联合处理协同地将GC细胞阻滞在G 0/G1期，下调GC相关蛋白的水平，包括阴离子交换蛋白1（AE 1）、细胞周期蛋白D1、β-连环蛋白和胞质p16，并促进p16的核转位。此外，联合治疗上调AE 2水平，其在GC组织中降低。在体内协同抗GC效应的联合治疗被证实在异种移植experiments.ConclusionsTrastuzumab加胃泌素抑制生长的Her 2阴性GC靶向细胞质AE 1和p16。
BackgroundAdministration of trastuzumab, a fully humanized monoclonal antibody targeted to the human epidermal growth factor receptor 2 (HER2, p185), has improved outcomes for patients with HER2-positive gastric cancer (GC), but some relevant issues remain to be investigated and will emerge with new anti-GC drugs. Gastrin is a major gastrointestinal hormone proven to have an inhibitory effect on GC in vitro and in vivo.AimTo explore the sympathetic role of trastuzumab and gastrin on inhibition of GC.MethodsThe HER2-positive and HER2-negative GC cell lines were treated with trastuzumab, gastrin, or their combination in vitro and in xenograft model. The synergistical role of trastuzumab and gastrin and related mechanisms were investigated.ResultsWe found the synergistic inhibitory effects of trastuzumab and gastrin on HER2-negative GC cells through the gastrin/cholecystokinin B receptor (CCKBR) pathway. Trastuzumab upregulated CCKBR protein levels but could not initiate its signal transduction, whereas gastrin increased the levels and activation of CCKBR. Molecular experiments indicated that trastuzumab and gastrin co-treatment synergistically enhanced the stability of CCKBR. Moreover, their combined treatment synergistically arrested GC cells at G0/G1 phase, down-regulated levels of GC-related proteins, including anion exchanger 1 (AE1), cyclin D1, β-catenin, and cytoplasmic p16, and promoted nuclear translocation of p16. In addition, combination treatment upregulated AE2 levels, which are reduced in GC tissues. The in vivo synergistic anti-GC effect of combined treatment was confirmed in xenograft experiments.ConclusionsTrastuzumab plus gastrin inhibit growth of Her2-negative GC by targeting cytoplasmic AE1 and p16.