Neuromedin B receptors regulate EGF receptor tyrosine phosphorylation in lung cancer cells.
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)alpha 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.
Moody
Terry W
TW
Department of Health and Human Services, National Cancer Institute, Center for Cancer Research, Office of the Director, Bethesda, Maryland 20892, USA. moodyt@mail.nih.gov
Berna
Marc J
MJ
Mantey
Samuel
S
Sancho
Veronica
V
Ridnour
Lisa
L
Wink
David A
DA
Chan
Daniel
D
Giaccone
Giuseppe
G
Jensen
Robert T
RT
D000111:Acetylcysteine / Q000494:pharmacology; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D000077156:Gefitinib; D006801:Humans; D015287:Neurokinin B / Q000031:analogs & derivatives / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D019000:Phosphotyrosine / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D018004:Receptors, Bombesin / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D011799:Quinazolines; D017382:Reactive Oxygen Species; D018004:Receptors, Bombesin; D019000:Phosphotyrosine; D015287:Neurokinin B; C038393:neuromedin B; D066246:ErbB Receptors; D000077156:Gefitinib; D000111:Acetylcysteine
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