title: Down-regulation of P-cadherin with PF-03732010 inhibits cell migration and tumor growth in gastric cancer.
abstract: P-cadherin is frequently up-regulated in solid tumors such as gastric, colon, lung, pancreatic and breast cancers. Although P-cadherin promotes cadherin-mediated cell adhesion, the gastric cancer-linked regulation of P-cadherin has not been extensively investigated. In this study, we found epigenetic regulation of P-cadherin in human gastric cancer cells that was induced by treatment with DNA demethylating drug and histone deacetylase inhibitor. Silencing P-cadherin by using siRNA induces apoptosis in gastric cells and blocks expression of Tie-2, an angiogenic receptor tyrosine kinase. In contrast, ectopically expressed P-cadherin by generating P-cadherin stable cell line enhances Tie-2 expression and cell mobility. We also demonstrated that inhibition of P-cadherin by PF-03732010, a fully humanized anti-P-cadherin IgG1 monoclonal antibody, suppressed cell migration in vitro and tumor growth in BALB/c nude mice bearing SNU620 gastric cancer xenograft. The data reported here are the first to reveal that the inhibition of P-cadherin decreases tumor cell migration and blocks a tumorigenesis by down-regulation of Tie-2 in gastric cancer. This demonstrates the potential for P-cadherin to be used as a target for treatment of gastric cancer.
authors: Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors: Jinah
authors: J
authors: Park
authors: Eunju
authors: E
authors: Park
authors: Sae-Won
authors: SW
authors: Han
authors: Seock-Ah
authors: SA
authors: Im
authors: Tae-You
authors: TY
authors: Kim
authors: Woo-Ho
authors: WH
authors: Kim
authors: Do-Youn
authors: DY
authors: Oh
authors: Yung-Jue
authors: YJ
authors: Bang
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology* / Q000627:therapeutic use; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D019175:DNA Methylation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects* / Q000235:genetics; D044127:Epigenesis, Genetic / Q000187:drug effects; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009361:Neoplasm Invasiveness; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D042787:Receptor, TIE-2; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D015820:Cadherins; C556089:PF-03732010 monoclonal antibody; D020794:Receptor Protein-Tyrosine Kinases; D042787:Receptor, TIE-2; C079086:Tek protein, mouse