HETEROLOGOUS DESENSITIZATION IN NEOPLASTIC THYROID-CELLS - INFLUENCE OF THE PHOSPHOLIPASE-C SIGNAL-TRANSDUCTION SYSTEM ON THE THYROTROPIN ADENYLATE-CYCLASE SIGNAL-TRANSDUCTION SYSTEM

Desensitization is defined as a decreased functional response after co ntinuous or repetitive stimulation of a receptor with its agonist. Thy rotropin (TSH) increases cAMP levels in normal and neoplastic thyroid tissue. The tumor promoter 12-O-tetradecanogl-phorbol-13-acetate (TPA) activates protein kinase C (PKC). The aim was to determine whether TP A induces heterologous desensitization of the TSM-adenylate cyclase (A C) signal transduction system, Three human thyroid neoplasms in cultur e for 6 months or longer tone papillary carcinoma, one Hurthle cell ca rcinoma, one follicular adenoma) were incubated with TSH (10 mU/ml) an d TPA (1.6 x 10(-8) M) separately and together for various time period s (from 10 minutes to 24 hours). The mixture mas subsequently incubate d for 30 minutes with TSH. TPA alone had no effect on cAMP Levels, but co-incubation of TPA and TSH caused a significant reduction in cAMP r esponse when compared to the cAMP response that resulted after stimula tion with only TSH (p < 0.001). cAMP levels in response to TSH decreas ed by 31%, 44%, and 57% after preincubation with TSH for 10 minutes, 4 hours, and 24 hours, respectively. cAMP Levels in response to TSH dec reased by 44%, 33%, and 29% after preincubation with TPA for 10 minute s, 4 hours, and 24 hours, respectively (p < 0.01; ANOVA), Go-incubatio n of cells with TPA and staurosporine (10 ng/ml), a PKC inhibitor, pre vented the effect of TPA on desensitization at 10 minutes and blunted the effect at 4 hours. This is the first demonstration in human neopla stic thyroid cells that TPA induced heterologous desensitization of th e cAMP response to TSH. This TPA-induced effect appears to involve PKC activation, as it can be blocked by staurosporine.