title: Lysophospholipids transactivate HER2/neu (erbB-2) in human gastric cancer cells.
abstract: The ligand-less receptor HER2/neu (erbB-2) has been proposed as a prognostic marker of gastric cancer that correlates with poor clinical outcome, indicating that HER2 signals play an important role in gastric cancer progression. This study demonstrated that two major natural lysophospholipids, lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P), induce rapid and transient phosphorylation of HER2 in two human gastric cancer cell lines, MKN28 and MKN74 cells. We also revealed that tyrosine phosphorylation of HER2 induced by both lysophospholipids was significantly attenuated by two inhibitors, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, AG1478, and a broad-spectrum matrix metalloproteinase inhibitor, GM6001. This suggests that the pathway of HER2 transactivation induced by these lysophospholipids is dependent on the proteolytically released EGFR ligands. Our results indicate that LPA and S1P act upstream of HER2 in gastric cancer cells, and thus may act as potent stimulators of gastric cancer.
authors.affiliation: Department of Surgical Oncology, University of Tokyo Graduate School of Medicine, Tokyo 113-8655, Japan. SHIDA-DIS@h.u-tokyo.ac.jp
authors.forename: Dai
authors.initials: D
authors.lastname: Shida
authors.forename: Joji
authors.initials: J
authors.lastname: Kitayama
authors.forename: Hironori
authors.initials: H
authors.lastname: Yamaguchi
authors.forename: Hiroharu
authors.initials: H
authors.lastname: Yamashita
authors.forename: Ken
authors.initials: K
authors.lastname: Mori
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Watanabe
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Nagawa
mesh_terms: D004591:Electrophoresis, Polyacrylamide Gel; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism; D018734:Genes, erbB-2; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism / Q000494:pharmacology*; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D013274:Stomach Neoplasms / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects*; D014407:Tumor Cells, Cultured
chemical_list: D004791:Enzyme Inhibitors; D066246:ErbB Receptors; D008246:Lysophospholipids; D008666:Metalloendopeptidases; D011505:Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D013110:Sphingosine; C060506:sphingosine 1-phosphate; C032881:lysophosphatidic acid