Somatostatin Inhibits PC Cl3 Thyroid Cell Proliferation through the Modulation of Phosphotyrosine Phosphatase Activity

Abstract

In this study, we report the effects of somatostatin on the proliferation of PC C13 thyroid cell line and the intracellular mechanisms involved. We also evaluated the possible alterations, induced by E1A oncogene transformation on the intracellular pathways mediating somatostatin inhibition of cell proliferation. We showed that somatostatin was able to powerfully inhibit insulin- and insulin + TSH-dependent cell proliferation by inducing a block in the G1/S progression in the cell cycle. These cytostatic effects were completely reverted by vanadate, suggesting that somatostatin may induce antiproliferative effects through the modulation of phosphotyrosine phosphatases. In the E1A-transformed cell line, somatostatin was completely ineffective. The lack of somatostatin inhibitory effects on cell proliferation were not due to alterations in the expression of somatostatin receptors, which were regularly expressed and coupled to adenylyl cyclase activity, but were dependent on an alteration in their coupling with the phosphotyrosine phosphatase. In fact, although in PC C13 cells somatostatin increased by 100% phosphotyrosine phosphatase activity, it was completely ineffective in E1A-expressing cells. In conclusion we demonstrated that somatostatin activates phosphotyrosine phosphatases in PC C13 thyroid cells to inhibit cell proliferation and that the stable expression of E1A oncogene in these cells completely abolishes this antiproliferative effect.

The Tyrosine Phosphatase SHP-1 Associates with the sst2 Somatostatin Receptor and Is an Essential Component of sst2-mediated Inhibitory Growth Signaling

“…We and others have demonstrated that somatostatin and analogues induce the stimulation of a membrane PTPase, which may be involved in the inhibitory effect of these peptides on cell proliferation (9,11,12,38). More recently, we have established the role of the somatostatin receptor sst2 in mediating the stimulatory effect of somatostatin on PTPase activity and its negative effect on cell growth (13,14).…”

Insulin and TSH promote growth in size of PC Cl3 rat thyroid cells, possibly via a pathway different from DNA synthesis: comparison with FRTL-5 cells

“…TSH activates proliferation through the adenylyl cyclase/cAMP cascade in rat thyroid cell lines (2)(3)(4)(5)(6). In addition, TSH, via cAMP, regulates mRNA expression of HMG-CoA reductase and an active cholesterol biosynthetic pathway is required for DNA replication in FRTL-5 cells (12,13).…”

“…As reported previously this cell line was derived from the thyroid of 3-to 4-week-old rats (2), whereas the other cell line investigated in the current study, PC Cl3, was derived from 18-month-old rat thyroid (3). While numerous reports show that in FRTL-5, and to a lesser extent in PC Cl3 rat thyroid cells, proliferation is regulated mainly by insulin or insulinlike growth factor (IGF) and thyrotropin (TSH) (2)(3)(4)(5)(6) the regulatory mechanisms of cell mass doubling are still unclear. Recently our laboratory has clearly shown that in primary cultures of dog thyroid cells, insulin promotes protein accumulation, while TSH, in the presence of insulin, triggers DNA synthesis (7).…”

Somatostatin Interferes with Thyrotropin-induced G1-S Transition Mediated by cAMP-dependent Protein Kinase and Phosphatidylinositol 3-Kinase

“…(8,13) and with an increase in the phosphorylation state of Rb (13), leading to the activation of cyclin⅐Cdk complexes and the progression of the cells through the cell cycle. TSH cell cycle induction is counteracted by cytostatic signals such as TGF-␤1 (13) and somatostatin (8,16,17). TGF-␤1 interference with TSH action has been studied in FRTL-5 cells (13); however, the mechanism of interference between somatostatin and TSH is unknown.…”