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Trastuzumab Inhibits Growth of HER2-Negative Gastric Cancer Cells Through Gastrin-Initialized CCKBR Signaling

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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.

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Acknowledgments

In vitro drug treatment and cell count experiments were aided by Dr. Ting Wang (Pathology Center, Shanghai Jiao Tong University School of Medicine). Flow cytometry work was assisted by Dong-Jun Qing (Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine). AE2 antibody was kindly provided by Professor Seth L. Alper (Beth Israel Deaconess Medical Center, Harvard Medical School). This work was supported in part by the National Natural Science Foundation of China (Nos. 81171939 and 81372637), The National Basic Research Program (973 Program, No. 2013CB910903), Key Projects in Shanghai Science & Technology Pillar Program for Biomedicine (No. 14431904700), Shanghai Science and Technology Yang Fan Funds (14YF1402300).

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    Authors and Affiliations

    1. Department of Oncology, Affiliated Hospital of Yanbian University, Yanbian, China

      Yan Cui

    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

      Yan Cui, Shao-Bo Li, **ng-Chun Peng, Jun Wu & Guo-Hui Fu

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    Correspondence to Jun Wu or Guo-Hui Fu.

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    Yan Cui and Shao-Bo Li have contributed equally to this work.

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    Cui, Y., Li, SB., Peng, XC. et al. Trastuzumab Inhibits Growth of HER2-Negative Gastric Cancer Cells Through Gastrin-Initialized CCKBR Signaling. Dig Dis Sci 60, 3631–3641 (2015). https://doi.org/10.1007/s10620-015-3793-7

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    • DOI: https://doi.org/10.1007/s10620-015-3793-7

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