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Potent Inhibition of Human Gastric Cancer by HER2-directed Induction of Apoptosis with Anti-HER2 Antibody and Caspase-3 Fusion Protein
  1. De-Xin Zhang1,
  2. Peng-Tao Zhao2,
  3. Lin Xia1,
  4. Hui-Hong Zhai1,
  5. Hong-Bo Zhang1,
  6. Xue-Gang Guo1,
  7. Kai-Chun Wu1,
  8. Yan-Ming Xu3,
  9. Lin-Tao Jia3,
  10. An-Gang Yang3,
  11. Si-Yi Chen4,
  12. Dai-Ming Fan1,*
  1. 1 Xijing Hospital of Digestive Disease, the Fourth Military Medical University, China;
  2. 2 Department of Pathology and Pathophysiology, the Fourth Military Medical University, China;
  3. 3 Department of Immunology, the Fourth Military Medical University, China;
  4. 4 Center for Cell and Gene Therapy, Baylor College of Medicine, United States
  1. Correspondence to: Dai-Ming Fan, Xijing Hospital of Digestive Disease, 15 West Chang-Le Road, Xi'an, 710032, China; fandaim{at}fmmu.edu.cn

Abstract

Background and aims: HER2 is an oncogene and has been found to be overexpressed in 10-40% of human gastric carcinomas. The aims of this study were to investigate if a fusion protein consisting of anti-HER2 sFv and constitutively active caspase-3 was capable of inducing apoptosis in HER2-expressing human gastric cancer cells and blocking the growth of human gastric cancer xenografts in nude mice.

Methods: NIH3T3 cells stably transduced with the pcDNA3.1-HER-PE-CP3 recombinant plasmid containing a secretion signal, a single-chain anti-HER2 monoclonal antibody fragment, a pseudomonas exotoxin A translocation domain and a constitutively-active caspase-3 molecule were used to induce apoptosis in human gastric cancer cells both in vitro and in vivo. Immunofluorescence staining and Western blotting were used to examine the expression of the recombinant protein HER-PE-CP3. The apoptosis was determined by flow cytometry and TUNEL assay.

Results: Co-cultivation of HER-PE-CP3/ NIH3T3 with human gastric cancer cells led to internalization of HER-PE-CP3 and apoptosis in HER2-expressing human gastric cancer cells but not in HER2-negative cancer cells. Inoculation of HER-PE-CP3/NIH3T3 in nude mice resulted in potent inhibition of human gastric cancer xenografts and much prolonged survival time of the tumor-bearing mice compared with the control. Significantly more apoptotic cells were detected in xenografts in mice receiving HER-PE-CP3/NIH3T3 than in control mice.

Conclusions: The HER-PE-CP3 chimerical molecule could induce selective apoptosis and potent growth inhibition of HER2-positive human gastric cancer cells and might represent a novel HER2-directed treatment option for human gastric cancer.

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