CHARACTERIZATION OF THE ANTIPROLIFERATIVE SIGNAL MEDIATED BY THE SOMATOSTATIN RECEPTOR SUBTYPE SST5

We investigated cell proliferation modulated by cholecystokinin (CCK) and somatostatin analogue RC-160 in CHO cells bearing endogenous CCKA receptors and stably transfected by human subtype sst5 somatostatin re ceptor, CCK stimulated cell proliferation of CHO cells, This effect wa s suppressed by inhibitor of the soluble guanylate cyclase, LY 83583, the inhibitor of the cGMP dependent kinases, KT 5823, and the inhibito r of mitogen-activated protein (MAP) kinase kinase, PD 98059, CCK trea tment induced an increase of intracellular cGMP concentrations, but co ncomitant addition of LY 83583 virtually suppressed this increase, CCK also activated both phosphorylation and activity of p42-MAP kinase; t hese effects were inhibited by KT 5823. All the effects of CCK depende d on a pertussis toxin-dependent G protein. Somatostatin analogue RC-1 60 inhibited CCK-induced stimulation of cell proliferation but it did not potentiate the suppressive effect of the inhibitors LY 83583 and K T 5823. RC-160 inhibited both CCK-induced intracellular cGMP formation as well as activation of p42-MAP kinase phosphorylation and activity, This inhibitory effect was observed at doses of RC-160 similar to tho se necessary to occupy the sst5 recombinant receptor and to inhibit CC K-induced cell proliferation, We conclude that, in CHO cells, the prol iferation and the MAP kinase signaling cascade depend on a cGMP-depend ent pathway, These effects are positively regulated by CCK and negativ ely influenced by RC-160. interacting through CCKA and sst5 receptors, respectively, These studies provide a characterization of the antipro liferative signal mediated by sst5 receptor.