Lysophospholipids transactivate HER2/neu (erbB-2) in human gastric cancer cells.
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.
Shida
Dai
D
Department of Surgical Oncology, University of Tokyo Graduate School of Medicine, Tokyo 113-8655, Japan. SHIDA-DIS@h.u-tokyo.ac.jp
Kitayama
Joji
J
Yamaguchi
Hironori
H
Yamashita
Hiroharu
H
Mori
Ken
K
Watanabe
Toshiaki
T
Nagawa
Hirokazu
H
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
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