Regulation of pancreastatin release from a human pancreatic carcinoid cell line in vitro.
The objective of these experiments was to investigate the influence of activation of three second messenger systems (protein kinase-C, adenylate cyclase-cAMP, and calcium mobilization) on the secretion of pancreastatin (PST) and chromogranin-A (CGA) by a human pancreatic carcinoid cell line (BON) in tissue culture. Stimulation of protein kinase-C by a phorbol ester (0.025-7.5 microM) caused a significant dose-related release of PST (186 +/- 22-4271 +/- 228% over controls). Treatment of BON cells with graded doses of 8-bromo-cAMP (0.14-3.0 mM) and isobutylmethylxanthine (IBMX; 0.01-1.0 mM) also stimulated a dose-related release of PST (107 +/- 22-284 +/- 28 and 16 +/- 12-1076 +/- 100% over controls, respectively). Incubation of BON cells with ionomycin (0.134-13.4 microM) increased the release of PST (102 +/- 15-554 +/- 21% over controls) in a dose-related manner. A combination of IBMX and ionomycin resulted in an additive effect, whereas treatment with a phorbol ester plus IBMX resulted in a synergistic effect on PST release. Pretreatment of BON cells with monensin, an agent that prevents processing of precursors to smaller peptides, significantly decreased PST, but not CGA, secretion in response to phorbol ester or ionomycin. These findings indicate that protein kinase-C, cAMP, and Ca2+ mobilization participate in CGA and PST secretion. Although the observation that secretions of PST and CGA in response to theophylline are quantitatively associated, the absence of a quantitative relationship in the release patterns of PST and CGA in response to phorbol ester and ionomycin do not support a simple precursor-product relationship between CGA and PST. The monensin experiments are consistent with the notion that PST is derived from CGA in BON cells.
Department of Surgery, University of Texas Medical Branch, Galveston 77550.
Y J
YJ
Jeng
C M
CM
Townsend
S
S
Nagasawa
S
S
Chuo
K
K
Kern
N
N
Yanaihara
R S
RS
Ferrar
F L
FL
Hill
J C
JC
Thompson
G H
GH
Greeley
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D002276:Carcinoid Tumor / Q000378:metabolism*; D002460:Cell Line; D002850:Chromatography, Gel; D053379:Chromogranin A; D002864:Chromogranins / Q000378:metabolism; D006801:Humans; D015759:Ionomycin / Q000494:pharmacology; D007700:Kinetics; D008985:Monensin / Q000494:pharmacology; D010187:Pancreatic Hormones / Q000302:isolation & purification / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D010703:Phorbol Esters / Q000494:pharmacology; D011863:Radioimmunoassay / Q000379:methods; D015290:Second Messenger Systems / Q000187:drug effects; D013806:Theophylline / Q000494:pharmacology
D053379:Chromogranin A; D002864:Chromogranins; D010187:Pancreatic Hormones; D010703:Phorbol Esters; C050836:pancreastatin; D015124:8-Bromo Cyclic Adenosine Monophosphate; D015759:Ionomycin; D008985:Monensin; D013806:Theophylline; D015056:1-Methyl-3-isobutylxanthine