Yan Cui1,2, Shao-Bo Li2, Xing-Chun Peng2, Jun Wu3, Guo-Hui Fu4. 1. Department of Oncology, Affiliated Hospital of Yanbian University, Yanbian, China. 2. Pathology Center, Shanghai First People's Hospital/Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Number 280, South Chong-Qing Road, Shanghai, 200025, China. 3. Pathology Center, Shanghai First People's Hospital/Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Number 280, South Chong-Qing Road, Shanghai, 200025, China. Jun.Wu@shsmu.edu.cn. 4. Pathology Center, Shanghai First People's Hospital/Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Number 280, South Chong-Qing Road, Shanghai, 200025, China. guohuifu@shsmu.edu.cn.
Abstract
BACKGROUND: Administration 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. AIM: To explore the sympathetic role of trastuzumab and gastrin on inhibition of GC. METHODS: The 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. RESULTS: We 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. CONCLUSIONS: Trastuzumab plus gastrin inhibit growth of Her2-negative GC by targeting cytoplasmic AE1 and p16.
BACKGROUND: Administration of trastuzumab, a fully humanized monoclonal antibody targeted to the humanepidermal 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. AIM: To explore the sympathetic role of trastuzumab and gastrin on inhibition of GC. METHODS: The 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. RESULTS: We 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. CONCLUSIONS:Trastuzumab plus gastrin inhibit growth of Her2-negative GC by targeting cytoplasmic AE1 and p16.
Entities:
Keywords:
Gastric cancer (GC); Gastrin; Gastrin/cholecystokinin B receptor (CCKBR); HER2; Trastuzumab
Authors: Y Yonemura; I Ninomiya; A Yamaguchi; S Fushida; H Kimura; S Ohoyama; I Miyazaki; Y Endou; M Tanaka; T Sasaki Journal: Cancer Res Date: 1991-02-01 Impact factor: 12.701
Authors: Hong-Jun Fei; Li-Dong Zu; Jun Wu; Xiao-Shu Jiang; Jing-Long Wang; Y Eugene Chin; Guo-Hui Fu Journal: Am J Cancer Res Date: 2016-12-01 Impact factor: 6.166