Receptor-mediated autocrine growth-stimulatory effect of 5-hydroxytryptamine on cultured human pancreatic carcinoid cells.
5-hydroxytryptamine (5-HT) is a mitogen for fibroblasts, vascular smooth muscle cells, renal mesangial cells, and jejunal crypt cells. The human carcinoid cell line (termed BON) that we established in our laboratory from a pancreatic carcinoid tumor produces and secretes 5-HT. In this study, therefore, we examined the effect of 5-HT on growth of BON cells. Furthermore, by use of selective 5-HT receptor antagonists, we examined receptor and post-receptor mechanisms by which 5-HT-induced responses were produced. 5-HT stimulated growth of BON cells. 5-HT stimulated phosphatidylinositol (PI) hydrolysis in a dose-dependent fashion and inhibited cyclic AMP production in a dose-dependent fashion. The 5-HT1A/1B receptor antagonist, SDZ 21-009, prevented the reduction of cyclic AMP production evoked by 5-HT and inhibited the mitogenic action of 5-HT. The 5-HT1C/2 receptor antagonist, mesulergine, competitively inhibited PI hydrolysis, but did not affect the mitogenic action of 5-HT. The mitogenic action of 5-HT and the reduction of cyclic AMP production evoked by 5-HT were also inhibited by pertussis toxin. These results suggest that 5-HT is an autocrine growth factor for BON cells and that mitogenic mechanism of 5-HT involves receptor-mediated inhibition of the production of cyclic AMP which may be linked to pertussis toxin-sensitive GTP binding protein. 8-bromo-cyclic AMP inhibited growth of BON cells whereas 8-bromo-cyclic GMP had no effect on cell growth. Involvement of protein kinase A in BON cell growth regulation was confirmed by the observation that a cAMP-dependent protein kinase antagonist (Rp-cAMPS) could stimulate BON cell growth.
Ishizuka
J
J
Department of Surgery, University of Texas Medical Branch, Galveston 77550.
Beauchamp
R D
RD
Townsend
C M
CM
Greeley
G H
GH
Thompson
J C
JC
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D000242:Cyclic AMP / Q000096:biosynthesis; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000494:pharmacology; D004873:Ergolines / Q000494:pharmacology; D006801:Humans; D010190:Pancreatic Neoplasms; D037342:Pertussis Toxin; D010716:Phosphatidylinositols / Q000096:biosynthesis; D010869:Pindolol / Q000031:analogs & derivatives / Q000494:pharmacology; D011985:Receptors, Serotonin / Q000378:metabolism*; D015290:Second Messenger Systems; D012701:Serotonin / Q000378:metabolism* / Q000494:pharmacology; D012702:Serotonin Antagonists; D014407:Tumor Cells, Cultured; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D004873:Ergolines; D010716:Phosphatidylinositols; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D010566:Virulence Factors, Bordetella; D015124:8-Bromo Cyclic Adenosine Monophosphate; C038186:4-(2-hydroxy-3-tert-butylaminopropoxy)-2-methylindole; C016276:8-bromocyclic GMP; D012701:Serotonin; D010869:Pindolol; D000242:Cyclic AMP; D037342:Pertussis Toxin; D006152:Cyclic GMP; C031649:mesulergine