title: Bombesin receptor subtype-3 agonists stimulate the growth of lung cancer cells and increase EGF receptor tyrosine phosphorylation.
abstract: The effects of bombesin receptor subtype-3 (BRS-3) agonists were investigated on lung cancer cells. The BRS-3 agonist (DTyr(6), (Ala(11), Phe(13), Nle(14)) bombesin(6-14) (BA1), but not gastrin releasing peptide (GRP) or neuromedin B (NMB) increased significantly the clonal growth of NCI-H1299 cells stably transfected with BRS-3 (NCI-H1299-BRS-3). Also, BA1 addition to NCI-H727 or NCI-H1299-BRS-3 cells caused Tyr(1068) phosphorylation of the epidermal growth factor receptor (EGFR). Similarly, (DTyr(6), R-Apa(11), Phe(13), Nle(14)) bombesin(6-14) (BA2) and (DTyr(6), R-Apa(11), 4-Cl,Phe(13), Nle(14)) bombesin(6-14) (BA3) but not gastrin releasing peptide (GRP) or neuromedin B (NMB) caused EGFR transactivation in NCI-H1299-BRS-3 cells. BA1-induced EGFR or ERK tyrosine phosphorylation was not inhibited by addition of BW2258U89 (BB(2)R antagonist) or PD168368 (BB(1)R antagonist) but was blocked by (DNal-Cys-Tyr-DTrp-Lys-Val-Cys-Nal)NH(2) (BRS-3 ant.). The BRS-3 ant. reduced clonal growth of NCI-H1299-BRS-3 cells. BA1, BA2, BA3 and BRS-3 ant. inhibit specific (125)I-BA1 binding to NCI-H1299-BRS-3 cells with an IC(50) values of 1.1, 21, 15 and 750nM, respectively. The ability of BRS-3 to regulate EGFR transactivation in NCI-H1299-BRS-3 cells was reduced by AG1478 or gefitinib (EGFR tyrosine kinase inhibitors), GM6001 (matrix metalloprotease inhibitor), PP2 (Src inhibitor), N-acetylcysteine (anti-oxidant), Tiron (superoxide scavenger) and DPI (NADPH oxidase inhibitor). These results demonstrate that BRS-3 agonists may stimulate lung cancer growth as a result of EGFR transactivation and that the transactivation is regulated by BRS-3 in a Src-, reactive oxygen and matrix metalloprotease-dependent manner.
authors.affiliation: Department of Health and Human Services, National Cancer Institute, Center for Cancer Research, Office of Director, Bethesda, MD 20892, USA. moodyt@mail.nih.gov
authors.forename: Terry W
authors.initials: TW
authors.lastname: Moody
authors.forename: Veronica
authors.initials: V
authors.lastname: Sancho
authors.forename: Alessia
authors.initials: A
authors.lastname: di Florio
authors.forename: Bernardo
authors.initials: B
authors.lastname: Nuche-Berenguer
authors.forename: Samuel
authors.initials: S
authors.lastname: Mantey
authors.forename: Robert T
authors.initials: RT
authors.lastname: Jensen
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D018004:Receptors, Bombesin / Q000819:agonists* / Q000037:antagonists & inhibitors; D015533:Transcriptional Activation
chemical_list: D047428:Protein Kinase Inhibitors; D018004:Receptors, Bombesin; C107120:bombesin receptor subtype 3; D066246:ErbB Receptors