title: Synergistic tumor suppression by adenovirus-mediated ING4/PTEN double gene therapy for gastric cancer.
abstract: Both inhibitor of growth 4 (ING4) and phosphatase and tensin homolog (PTEN) have been shown to be strong candidate tumor suppressors. However, the combined efficacy of ING4 and PTEN for human gastric cancer remains to be determined. In this report, we constructed a multiple promoter expression cassette-based recombinant adenovirus coexpressing ING4 and PTEN (AdVING4/PTEN), assessed the combined effects of AdVING4/PTEN on gastric cancer using wild-type p53 AGS and SNU-1 human gastric cancer cell lines, and elucidated its underlying mechanisms. We found that AdVING4/PTEN-induced synergistic growth inhibition and apoptosis in vitro AGS or SNU-1 tumor cells and in vivo AGS xenografted tumors subcutaneously inoculated in athymic BALB/c nude mice. Mechanistically, AdVING4/PTEN exhibited an enhanced effect on upregulation of p53, Ac-p53 (K382), P21, Bax, PUMA, Noxa, cleaved Caspase-9, cleaved Caspase-3 and cleaved PARP as well as downregulation of Bcl-2 in vitro and in vivo. In addition, AdVING4/PTEN synergistically downregulated tumor vessel CD34 expression and reduced microvessel density, and additively inhibited vascular endothelial growth factor (VEGF) expression in vivo. The synergistic tumor suppression elicited by AdVING4/PTEN was closely associated with the synergistic induction of apoptosis possibly via enhancement of endogenous p53 responses through cooperatively facilitating p53's stability and acetylation, and the synergistic inhibition of tumor angiogenesis probably via overlapping reduction of VEGF through cooperatively downregulating hypoxia inducible factor-1α's level and transcription activity. Thus, our results indicate that cancer gene therapy combining ING4 and PTEN may constitute a novel and effective therapeutic modality for human gastric cancer and other cancers.
authors.affiliation: Department of General Surgery, the First Affiliated Hospital of Soochow University, Suzhou, China.
authors.forename: H
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Oncology, the First Affiliated Hospital of Soochow University, Suzhou, China.
authors.forename: X
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Oncology, the First Affiliated Hospital of Soochow University, Suzhou, China.
authors.forename: C
authors.initials: C
authors.lastname: Xu
authors.affiliation: Department of Cell Biology, College of Medicine, Soochow University, Suzhou, China.
authors.forename: J
authors.initials: J
authors.lastname: Yang
authors.affiliation: Cancer Research Unit, Saskatchewan Cancer Agency, Saskatoon, Saskatchewan, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Xiang
authors.affiliation: Department of Oncology, the First Affiliated Hospital of Soochow University, Suzhou, China.
authors.forename: M
authors.initials: M
authors.lastname: Tao
authors.affiliation: Department of Oncology, the First Affiliated Hospital of Soochow University, Suzhou, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Xie
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D017209:Apoptosis; D018797:Cell Cycle Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D015316:Genetic Therapy; D005822:Genetic Vectors; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D013274:Stomach Neoplasms / Q000098:blood supply / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D014161:Transduction, Genetic; D019076:Transgenes; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D018797:Cell Cycle Proteins; D018398:Homeodomain Proteins; C483230:ING4 protein, human; D025521:Tumor Suppressor Proteins; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human