Novel action of transforming growth factor beta 1 in functioning human pancreatic carcinoid cells.
We have shown recently that 5-HT is an autocrine growth stimulatory factor for a cell line (BON) that is derived from a human pancreatic carcinoid tumor. This action is mediated by a 5-HT receptor-linked decrease of cyclic adenosine monophosphate (AMP) production, but not mediated by a 5-HT receptor-linked stimulation of phosphatidylinositol hydrolysis. The BON cells also express transforming growth factor betas (TGF beta s) (1, 2, and 3) and release TGF beta into their medium. In this study, we examined the effects of TGF beta on the secretion of 5-HT, on signal transduction pathways involved in 5-HT secretion, and on growth of BON cells. TGF beta 1 inhibited basal and acetylcholine-stimulated release of 5-HT, but did not inhibit isobutylmethylxanthine-stimulated release of 5-HT. TGF beta 1 inhibited both basal and acetylcholine-stimulated hydrolysis of phosphatidylinositol in a dose dependent manner, but did not affect cyclic AMP production. TGF-beta 1 inhibited growth of BON cells in culture; this effect was reversed by exogenously administered 5-HT. Three different specific and saturable TGF beta 1 binding sites were identified; binding assays performed after mild acid wash (0.1% acetic acid, pH 2.5) conditions uncovered TGF beta receptors that were apparently occupied by endogenously produced TGF beta species. Affinity cross-linking assay showed that BON cells had three different TGF beta binding proteins. These results suggest that TGF beta 1 can inhibit growth of BON cells by altering secretory responses of 5-HT by means of receptor-mediated inhibition of phosphatidylinositol hydrolysis. We conclude that growth of BON cells is regulated, at least in part, by the opposing receptor-mediated autocrine actions of 5-HT and TGF beta.
Department of Surgery, University of Texas Medical Branch, Galveston 77555-0533.
J
J
Ishizuka
R D
RD
Beauchamp
K
K
Sato
C M
CM
Townsend
J C
JC
Thompson
D000345:Affinity Labels; D002276:Carcinoid Tumor / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D008297:Male; D010190:Pancreatic Neoplasms / Q000473:pathology*; D010716:Phosphatidylinositols / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta; D012701:Serotonin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000345:Affinity Labels; D010716:Phosphatidylinositols; D011956:Receptors, Cell Surface; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D012701:Serotonin; D000242:Cyclic AMP