title: CI-988 Inhibits EGFR Transactivation and Proliferation Caused by Addition of CCK/Gastrin to Lung Cancer Cells.
abstract: Cholecystokinin (CCK) receptors are G-protein coupled receptors (GPCR) which are present on lung cancer cells. CCK-8 stimulates the proliferation of lung cancer cells, whereas the CCK2R receptor antagonist CI-988 inhibits proliferation. GPCR for some gastrointestinal hormones/neurotransmitters mediate lung cancer growth by causing epidermal growth factor receptor (EGFR) transactivation. Here, the role of CCK/gastrin and CI-988 on EGFR transactivation and lung cancer proliferation was investigated. Addition of CCK-8 or gastrin-17 (100 nM) to NCI-H727 human lung cancer cells increased EGFR Tyr(1068) phosphorylation after 2 min. The ability of CCK-8 to cause EGFR tyrosine phosphorylation was blocked by CI-988, gefitinib (EGFR tyrosine kinase inhibitor), PP2 (Src inhibitor), GM6001 (matrix metalloprotease inhibitor), and tiron (superoxide scavenger). CCK-8 nonsulfated and gastrin-17 caused EGFR transactivation and bound with high affinity to NCI-H727 cells, suggesting that the CCK2R is present. CI-988 inhibited the ability of CCK-8 to cause ERK phosphorylation and elevate cytosolic Ca(2+). CI-988 or gefitinib inhibited the basal growth of NCI-H727 cells or that stimulated by CCK-8. The results indicate that CCK/gastrin may increase lung cancer proliferation in an EGFR-dependent manner.
authors.affiliation: Department of Health and Human Services, National Cancer Institute, Center for Cancer Research, Office of the Director, 9609 Medical Center Drive, Room 2 W-130, Bethesda, MD, 20892, USA, moodyt@mail.nih.gov.
authors.forename: Terry W
authors.initials: TW
authors.lastname: Moody
authors.forename: Bernardo
authors.initials: B
authors.lastname: Nuche-Berenguer
authors.forename: Paola
authors.initials: P
authors.lastname: Moreno
authors.forename: Robert T
authors.initials: RT
authors.lastname: Jensen
mesh_terms: D014013:1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004151:Dipeptides / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism*; D005755:Gastrins / Q000494:pharmacology*; D000077156:Gefitinib; D006727:Hormone Antagonists / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000378:metabolism*; D008536:Meglumine / Q000031:analogs & derivatives* / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology
chemical_list: C412373:AG 1879; D000970:Antineoplastic Agents; D004151:Dipeptides; D005755:Gastrins; D006727:Hormone Antagonists; D007211:Indoles; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D011743:Pyrimidines; D011799:Quinazolines; C065599:PD 134308; D014013:1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt; C013550:gastrin 17; D008536:Meglumine; D066246:ErbB Receptors; D000077156:Gefitinib