SOMATOSTATIN INHIBITS PC C-13 THYROID-CELL PROLIFERATION THROUGH THE MODULATION OF PHOSPHOTYROSINE PHOSPHATASE-ACTIVITY - IMPAIRMENT OF THESOMATOSTATINERGIC EFFECTS BY STABLE EXPRESSION OF E1A VIRAL ONCOGENE

In this study, we report the effects of somatostatin on the proliferat ion of PC Cl3 thyroid cell line and the intracellular mechanisms invol ved. We also evaluated the possible alterations, induced by E1A oncoge ne transformation on the intracellular pathways mediating somatostatin inhibition of cell proliferation. We showed that somatostatin was abl e to powerfully inhibit insulin- and insulin + TSH-dependent cell prol iferation by in ducing a block in the G(1)/S progression in the cell c ycle. These cytostatic effects were completely reverted by vanadate, s uggesting that somatostatin may induce antiproliferative effects throu gh the modulation of phosphotyrosine phosphatases. In the E1A-transfor med cell line, somatostatin was completely ineffective. The lack of so matostatin inhibitory effects on cell proliferation were not due to al terations in the expression of somatostatin receptors, which were regu larly expressed and coupled to adenylyl cyclase activity, but were dep endent on an alteration in their coupling with the phosphotyrosine pho sphatase. In fact, although in PC Cl3 cells somatostatin increased by 100% phosphotyrosine phosphatase activity, it was completely ineffecti ve in E1A-expressing cells. In conclusion we demonstrated that somatos tatin activates phosphotyrosine phosphatases in PC Cl3 thyroid cells t o inhibit cell proliferation and that the stable expression of E1A onc ogene in these cells completely abolishes this antiproliferative effec t.