Divergent proliferative responses to a gastrin receptor ligand in synchronized and unsynchronized rat pancreatic AR42J tumour cells.
Depending upon experimental model, the CCK-B/gastrin receptor ligand CI-988 exhibits either agonist or antagonist activity. To confirm that CI-988 behaves as an antagonist toward gastrin-stimulated growth, its effects on cell proliferation were investigated in unsynchronized and synchronized AR42J rat pancreatic tumour cells. In unsynchronized cultures CI-988 alone had no effect, but inhibited gastrin-stimulated cell proliferation. In contrast, in synchronized cultures, CI-988 stimulated cell proliferation. Similarly, CI-988 inhibited gastrin-stimulated cAMP production in unsynchronized cells, but stimulated cAMP formation in synchronized cultures. Therefore, CI-988 stimulation of cAMP production and proliferation in AR42J cell cultures appears to be cell cycle-dependent. CI-988 inhibited gastrin-stimulated intracellular calcium ([Ca2+]i) mobilization in both populations and thus acted as an antagonist toward this pathway. Because CCK receptor densities and affinities were similar in both cell populations, the data suggest that CI-988's divergent effects on cell proliferation are governed by postreceptor signalling events which vary with cell cycle.
Bestervelt
L
L
Department of Pathology and Experimental Toxicology, Parke-Davis Pharmaceutical Research, Ann Arbor, MI 48105, USA.
Barr
B
B
Dethloff
L
L
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D005755:Gastrins / Q000378:metabolism / Q000494:pharmacology; D006727:Hormone Antagonists / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D008024:Ligands; D008536:Meglumine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D011949:Receptors, Cholecystokinin / Q000819:agonists* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D005755:Gastrins; D006727:Hormone Antagonists; D007211:Indoles; D008024:Ligands; D011949:Receptors, Cholecystokinin; C065599:PD 134308; D008536:Meglumine