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.