Neuromedin B receptors regulate EGF receptor tyrosine phosphorylation in lung cancer cells

• Published in: European journal of pharmacology 2010-07, Vol.637 (1), p.38-45
• Main Authors: Moody, Terry W., Berna, Marc J., Mantey, Samuel, Sancho, Veronica, Ridnour, Lisa, Wink, David A., Chan, Daniel, Giaccone, Giuseppe, Jensen, Robert T.
• Format: Article
• Language: English
• Subjects: Acetylcysteine - pharmacology; Biological and medical sciences; Blotting, Western; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - pathology; Enzyme Inhibitors - pharmacology; Epidermal growth factor receptor; ErbB Receptors - drug effects; ErbB Receptors - genetics; ErbB Receptors - metabolism; Gefitinib; Humans; Lung cancer; Medical sciences; Neurokinin B - analogs & derivatives; Neurokinin B - pharmacology; Neuromedin B; Pharmacology. Drug treatments; Phosphorylation - drug effects; Phosphotyrosine - metabolism; Pneumology; Quinazolines - pharmacology; Reactive oxygen species; Reactive Oxygen Species - metabolism; Receptors, Bombesin - genetics; Receptors, Bombesin - metabolism; Transactivation; Transcriptional Activation - drug effects; Transcriptional Activation - physiology; Tumor Cells, Cultured; Tumors of the respiratory system and mediastinum
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2010.03.057

Neuromedin B (NMB), a member of the bombesin family of peptides, is an autocrine growth factor for many lung cancer cells. The present study investigated the ability of NMB to cause transactivation of the epidermal growth factor (EGF) receptor in lung cancer cells. By Western blot, addition of NMB or related peptides to NCI-H1299 human non-small cell lung cancer (NSCLC) cells, caused phosphorylation of Tyr 1068 of the EGF receptor. The signal was amplified using NCI-H1299 cells stably transected with NMB receptors. The transactivation of the EGF receptor or the tyrosine phosphorylation of ERK caused by NMB-like peptides was inhibited by AG1478 or gefitinib (tyrosine kinase inhibitors) and NMB receptor antagonist PD168368 but not the GRP receptor antagonist, BW2258U89. The transactivation of the EGF receptor caused by NMB-like peptides was inhibited by GM6001 (matrix metalloprotease inhibitor), PP2 (Src inhibitor), or transforming growth factor (TGF)α antibody. The transactivation of the EGF receptor and the increase in reactive oxygen species caused by NMB-like peptides was inhibited by N-acetylcysteine (NAC) or Tiron. Gefitinib inhibited the proliferation of NCI-H1299 cells and its sensitivity was increased by the addition of PD168368. The results indicate that the NMB receptor regulates EGF receptor transactivation by a mechanism dependent on Src as well as metalloprotease activation and generation of reactive oxygen species.