Somatostatin receptors 1, 2, and 5 cooperate in the somatostatin inhibition of C6 glioma cell proliferation in vitro via a phosphotyrosine phosphatase-eta-dependent inhibition of extracellularly regulated kinase-1/2.

Somatostatin inhibits cell proliferation through the activation of five receptors expressed in normal and cancer cells. We analyzed the role of individual 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 -2, and -5) and octreotide. The activation of was ineffective, although all duanyu1942Rs are functionally active, as demonstrated by the inhibition of cAMP production. All duanyu1942Rs induced cytostatic effects through the activation of the phosphotyrosine phosphatase PTPeta and the inhibition of ERK1/2. For possible synergism between subtypes, we tested the effects of the combined treatment with two agonists or or bifunctional compounds. The simultaneous activation of and slightly increased the efficacy of the individual compounds with an IC50 in between the single receptor activation. activation displayed a pattern of response superimposable to that of the agonist alone (low potency and higher efficacy, as compared with BIM-23120). The simultaneous activation of duanyu1942R1, -2, and -5 resulted in a response similar to somatostatin. In conclusion, the cytostatic effects of somatostatin in C6 cells are mediated by the duanyu1942R1, -2, and -5 through the same intracellular pathway: activation of PTPeta and inhibition of ERK1/2 activity. Somatostatin is more effective than the individual agonists. The combined activation of duanyu1942R1 and -2 shows a partial synergism as far as antiproliferative activity, whereas duanyu1942R2 and -5 activation results in a response resembling the duanyu1942R5 effects.

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