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Stepan, VM; Sawada, M; Todisco, A; Dickinson, CJ.
Glycine-extended gastrin exerts growth-promoting effects on human colon cancer cells.
Mol Med. 1999; 5(3):147-159 Doi: 10.1007/BF03402058 [OPEN ACCESS]
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Leading authors Med Uni Graz: Stepan Vinzenz
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Abstract:: BACKGROUND: Since human colon cancers often contain significant quantities of progastrin-processing intermediates, we sought to explore the possibility that the biosynthetic precursor of fully processed amidated gastrin, glycine-extended gastrin, may exert trophic effects on human colonic cancer cells. MATERIALS AND METHODS: Binding of radiolabeled glycine-extended and amidated gastrins was assessed on five human cancer cell lines: LoVo, HT 29, HCT 116, Colo 320DM, and T 84. Trophic actions of the peptides were assessed by increases in [3H]thymidine incorporation and cell number. Gastrin expression was determined by northern blot and radioimmunoassay. RESULTS: Amidated gastrin did not bind to or stimulate the growth of any of the five cell lines. In contrast, saturable binding of radiolabeled glycine-extended gastrin was seen on LoVo and HT 29 cells that was not inhibited by amidated gastrin (10(-6) M) nor by a gastrin/CCKB receptor antagonist (PD 134308). Glycine-extended gastrin induced a dose-dependent increase in [3H]thymidine uptake in LoVo (143 +/- 8% versus control at 10(-10) M) and HT 29 (151 +/- 11% versus control at 10(-10) M) cells that was not inhibited by PD 134308 or by a mitogen-activated protein (MAP) or ERK kinase (MEK) inhibitor (PD 98509). Glycine-extended gastrin did stimulate jun-kinase activity in LoVo and HT 29 cells. The two cell lines expressed the gastrin gene at low levels and secreted small amounts of amidated gastrin and glycine-extended gastrin into the media. CONCLUSIONS: Glycine-extended gastrin receptors are present on human colon cancer cells that mediate glycine-extended gastrin's trophic effects via a MEK-independent mechanism. This suggests that glycine-extended gastrin and its novel receptors may play a role in colon cancer cell growth.
Find related publications in this database (using NLM MeSH Indexing): Animals -; Antineoplastic Agents - pharmacology; Binding Sites -; Binding, Competitive -; Calcium-Calmodulin-Dependent Protein Kinases - drug effects Calcium-Calmodulin-Dependent Protein Kinases - metabolism; Cell Division - drug effects; Colonic Neoplasms - drug therapy Colonic Neoplasms - metabolism Colonic Neoplasms - pathology; DNA-Binding Proteins -; Dose-Response Relationship, Drug -; Enzyme Inhibitors - pharmacology; Flavonoids - pharmacology; Gastrins - genetics Gastrins - metabolism Gastrins - pharmacology; Gene Expression Regulation - drug effects; Humans -; Indoles - pharmacology; JNK Mitogen-Activated Protein Kinases -; Meglumine - analogs and derivatives Meglumine - pharmacology; Mitogen-Activated Protein Kinases -; Peptide Fragments - metabolism Peptide Fragments - pharmacology; Protein Processing, Post-Translational -; Proto-Oncogene Proteins - drug effects Proto-Oncogene Proteins - genetics Proto-Oncogene Proteins - metabolism; Rats -; Receptors, Cholecystokinin - drug effects Receptors, Cholecystokinin - metabolism; Recombinant Proteins - drug effects Recombinant Proteins - genetics Recombinant Proteins - metabolism; Response Elements -; Signal Transduction -; Tetradecanoylphorbol Acetate - pharmacology; Transcription Factors -; Tumor Cells, Cultured -; ets-Domain Protein Elk-1 -