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Role of Complex Cyclin D1/Cdk4 in Somatostatin Subtype 2 Receptor-Mediated Inhibition of Cell Proliferation of a Medullary Thyroid Carcinoma Cell Line in Vitro

Section of Endocrinology (F.T., M.C.Z., A.B., D.P., A.L., E.C.d.U.), Department of Biomedical Sciences and Advanced Therapies, University of Ferrara, I-44100 Ferrara, Italy; and Biomeasure Inc./IPSEN (M.D.C.), Milford, Massachusetts 01757

Address all correspondence and requests for reprints to: Ettore C. degli Uberti, M.D., Section of Endocrinology, Department of Biomedical Sciences and Advanced Therapies, University of Ferrara, Via Savonarola 9, 44100 Ferrara, Italy. E-mail: ti8{at}unife.it.

Somatostatin (SRIH) inhibits cell proliferation by interacting with five distinct SRIH receptor subtypes (SSTRs) activating several pathways in many tissues. We previously demonstrated that SRIH, by activating Src homology-2-containing protein, inhibits cell proliferation of the human medullary thyroid carcinoma cell line, TT, which expresses all SSTRs. However, the effects of SRIH on cell cycle proteins have not been investigated so far. We therefore evaluated the effects of SRIH and a selective SSTR2 agonist on cell cycle protein expression, mainly focusing on cyclin D1 and its associated kinases. Our data show that SRIH and the selective SSTR2 agonist, BIM-23120, reduce cell proliferation and DNA synthesis as well as induce a delay of the cell cycle in G₂/M phase. Moreover, treatment with both SRIH and BIM-23120 decreases cyclin D1 levels, with a parallel increase in phosphocyclin D1 levels, suggesting protein degradation. Moreover, our data show an increase in glycogen synthase kinase-3ß activity, which triggers phosphorylation-dependent cyclin D1 degradation. Indeed, we observed a reduction in cyclin D1 protein half-life under treatment with SRIH or the SSTR2 selective agonist. A reduction in cdk4 protein levels is also observed with a parallel reduction in Rb phosphorylation levels at Ser-780. Our data indicate that the subtype 2 receptor-mediated antiproliferative effect of SRIH on TT cell proliferation may be exerted through a decrease in cyclin D1 levels.

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