The phosphotyrosine phosphatase eta mediates somatostatin inhibition of glioma proliferation via the dephosphorylation of ERK1/2.
Somatostatin (SST) controls the proliferation of a variety of cell types. Its effects are mediated by five G protein-coupled receptors (SSTR1-SSTR5), variably expressed in normal and cancer tissues. SST inhibition of cell proliferation can be exploited by both direct and indirect mechanisms: the main direct pathway involves the modulation of phosphotyrosine phosphatase (PTP) activity. Here we show that SST cytostatic activity is mediated by the activation of a receptor-like PTP, named PTPeta. The role of this PTP in the antiproliferative activity of SST in five glioma cell lines (C6, U87MG, U373MG, DBTRG05MG, and CAS1) and in four postsurgical human glioblastoma specimens, has been studied. SST inhibited growth only in C6 and U87MG that express PTPeta. In C6 cells, SST antiproliferative effects were reverted by pretreatment with pertussis toxin and vanadate, indicating the involvement of G proteins and PTPs. The role of PTPeta in the SST inhibitory effects was demonstrated by testing the PTPeta activity: it was increased by SST treatment and paralleled by inhibition of ERK1/2 activation. Since basic fibroblast growth factor-dependent MEK phosphorylation was not affected by SST, we propose a direct effect of SST-activated PTPeta on ERK1/2 phosphorylation. Finally, the SSTR mRNAs were identified in all of the 36 gliomas analyzed, whereas PTPeta expression was found in 33% of cases. Culturing four gliomas, a precise correlation between the expression of PTPeta and the SST antiproliferative effects was identified. In conclusion, in glioma cells, SST antiproliferative activity requires the expression and activation of PTPeta, which directly dephosphorylates ERK1/2.
Massa
Alessandro
A
Section of Pharmacology, Department of Oncology, Biology, and Genetics, University of Genova, Largo R. Benzi 10, 16132 Genova, Italy.
Barbieri
Federica
F
Aiello
Cinzia
C
Iuliano
Rodolfo
R
Arena
Sara
S
Pattarozzi
Alessandra
A
Corsaro
Alessandro
A
Villa
Valentina
V
Fusco
Alfredo
A
Zona
Gianluigi
G
Spaziante
Renato
R
Schettini
Gennaro
G
Florio
Tullio
T
D001932:Brain Neoplasms / Q000201:enzymology / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005910:Glioma / Q000201:enzymology / Q000473:pathology*; D006801:Humans; D047468:Immunoprecipitation; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013004:Somatostatin / Q000502:physiology*
D013004:Somatostatin; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D017027:Protein Tyrosine Phosphatases; C453859:phosphotyrosine phosphatase eta