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Somatostatin Receptors 1, 2, and 5 Cooperate in the Somatostatin Inhibition of C6 Glioma Cell Proliferation in Vitro via a Phosphotyrosine Phosphatase--Dependent Inhibition of Extracellularly Regulated Kinase-1/2

Laboratory of Pharmacology (F.B., A.P., M.G., C.P., A.B., T.F.), Department of Oncology, Biology and Genetics, University of Genova, 16132 Genova, Italy; Istituto Zooprofilattico Sperimentale del Piemonte (A.F.), Liguria e Valle D'Aosta, National Reference Center of Veterinary and Comparative Oncology, 16132 Genova, Italy; and IPSEN (M.D.C.), Milford, Massachusetts 01757

Address all correspondence and requests for reprints to: Prof. Tullio Florio, Department of Oncology, Biology, and Genetics, University of Genova, Viale Benedetto XV, 2, 16132 Genova, Italy. E-mail: tullio.florio{at}unige.it.

Somatostatin inhibits cell proliferation through the activation of five receptors (SSTR1–5) expressed in normal and cancer cells. We analyzed the role of individual SSTRs in the antiproliferative activity of somatostatin in C6 rat glioma cells. Somatostatin dose-dependently inhibited C6 proliferation, an effect mimicked, with different efficacy or potency, by BIM-23745, BIM-23120, BIM-23206 (agonists for SSTR1, -2, and -5) and octreotide. The activation of SSTR3 was ineffective, although all SSTRs are functionally active, as demonstrated by the inhibition of cAMP production. All SSTRs induced cytostatic effects through the activation of the phosphotyrosine phosphatase PTP and the inhibition of ERK1/2. For possible synergism between SSTR subtypes, we tested the effects of the combined treatment with two agonists (SSTR1+2 or SSTR2+5) or bifunctional compounds. The simultaneous activation of SSTR1 and SSTR2 slightly increased the efficacy of the individual compounds with an IC₅₀ in between the single receptor activation. SSTR2+5 activation displayed a pattern of response superimposable to that of the SSTR5 agonist alone (low potency and higher efficacy, as compared with BIM-23120). The simultaneous activation of SSTR1, -2, and -5 resulted in a response similar to somatostatin. In conclusion, the cytostatic effects of somatostatin in C6 cells are mediated by the SSTR1, -2, and -5 through the same intracellular pathway: activation of PTP and inhibition of ERK1/2 activity. Somatostatin is more effective than the individual agonists. The combined activation of SSTR1 and -2 shows a partial synergism as far as antiproliferative activity, whereas SSTR2 and -5 activation results in a response resembling the SSTR5 effects.