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 (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 PTPeta 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 PTPeta 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.
Laboratory pf Pharmacology, Department of Oncology, Biology, and Genetics, University of Genova, Viale Benedetto XV, 2, 16132 Genova, Italy.
Federica
F
Barbieri
Alessandra
A
Pattarozzi
Monica
M
Gatti
Carola
C
Porcile
Adriana
A
Bajetto
Angelo
A
Ferrari
Michael D
MD
Culler
Tullio
T
Florio
D000818:Animals; D016466:CHO Cells; D049109:Cell Proliferation / Q000187:drug effects*; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D005910:Glioma / Q000473:pathology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000502:physiology*; D051381:Rats; D017481:Receptors, Somatostatin / Q000819:agonists / Q000502:physiology*; D013004:Somatostatin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D017481:Receptors, Somatostatin; C101130:somatostatin receptor type 1; D013004:Somatostatin; C094573:somatostatin receptor 5; C093733:somatostatin receptor 2; D000242:Cyclic AMP; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D017027:Protein Tyrosine Phosphatases; C453859:phosphotyrosine phosphatase eta