Desensitization is defined as a decreased functional response after continuous or repetitive stimulation of a receptor with its agonist. Thyrotropin (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 TPA induces heterologous desensitization of the TSM-adenylate cyclase (AC) signal transduction system, Three human thyroid neoplasms in culture for 6 months or longer tone papillary carcinoma, one Hurthle cell carcinoma, one follicular adenoma) were incubated with TSH (10 mU/ml) and TPA (1.6 x 10(-8) M) separately and together for various time periods (from 10 minutes to 24 hours). The mixture mas subsequently incubated 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 response when compared to the cAMP response that resulted after stimulation with only TSH (p < 0.001). cAMP levels in response to TSH decreased by 31%, 44%, and 57% after preincubation with TSH for 10 minutes, 4 hours, and 24 hours, respectively. cAMP Levels in response to TSH decreased by 44%, 33%, and 29% after preincubation with TPA for 10 minutes, 4 hours, and 24 hours, respectively (p < 0.01; ANOVA), Go-incubation of cells with TPA and staurosporine (10 ng/ml), a PKC inhibitor, prevented the effect of TPA on desensitization at 10 minutes and blunted the effect at 4 hours. This is the first demonstration in human neoplastic thyroid cells that TPA induced heterologous desensitization of the cAMP response to TSH. This TPA-induced effect appears to involve PKC activation, as it can be blocked by staurosporine.