Somatostatin is expressed in FRTL-5 thyroid cells and prevents thyrotropin-mediated down-regulation of the cyclin-dependent kinase inhibitor p27(kip1)

Using RT and amplification, we have detected specific RNA transcripts encod ing somatostatin in FRTL-5 thyroid cells. This observation indicates that w ithin the thyroid context, expression of somatostatin is not restricted to the parafollicular C cells. Transfection of FRTL-5 cells with constructs co ntaining either the complete somatostatin gene promoter or deletions carryi ng the cAMP response element-binding site allowed us to demonstrate that tr anscription of the somatostatin gene is hormonally regulated by TSH. Blocka ge of somatostatin by specific antibodies resulted in an increased capacity of TSH-induced FRTL-5 cell-conditioned medium to promote cell proliferatio n, demonstrating that under physiological conditions, somatostatin exerts a cytostatic effect on FRTL-5 cells growth. Somatostatin treatment of FRTL-5 cells resulted in a growth retardation, caused by a dose-response delay in the G(1) phase of the cell cycle. This effect appears to be mediated by th e cyclin-dependent kinase inhibitor p27(kip1), which is clearly down-regula ted in FRTL-5 cells treated with TSH and whose expression is reestablished by somatostatin in a dose-dependent manner. Participation of somatostatin i n the control of FRTL-5 cell proliferation is in agreement with the detecti on of specific somatostatin receptor type 2. Flow cytometric assays reveal that FRTL-5 cells transformed with the K-ras oncogene are still sensitive t o somatostatin treatment, whereas fully neoplastic FRT cells no longer resp ond to this peptide. Taking together, the results demonstrate the participa tion of an autocrine loop in the control of thyroid cell proliferation, and the possibility that this mechanism could be altered in the process of thy roid carcinogenesis.