The expression of the phosphotyrosine phosphatase DEP-1/PTPeta dictates the responsivity of glioma cells to somatostatin inhibition of cell proliferation.
Here we characterize the intracellular effectors of the antiproliferative activity of somatostatin in glioma cell lines and post-surgical specimens. The responsiveness to somatostatin correlated with the expression of the phosphotyrosine phosphatase DEP-1/PTPeta, identified in C6 and U87MG cells, in which somatostatin inhibited cell growth. The expression of a dominant negative mutant of DEP-1/PTPeta in C6 cells abolished somatostatin effects, confirming the involvement of this phosphotyrosine phosphatase in such effects. Somatostatin treatment increased the activity of DEP-1/PTPeta and inhibited ERK1/2 activation. Conversely, basic fibroblast growth factor-dependent MEK phosphorylation was not affected, suggesting a direct effect on ERK1/2. In vitro experiments showed that PTPeta was able to interact and dephosphorylate ERK1/2 activated by basic fibroblast growth factor. Furthermore, by transfecting PTPeta in the somatostatin-unresponsive, DEP-1/PTPeta-deficient U373MG cells, the somatostatin-dependent control of cell proliferation was recovered. Finally we evaluated the requirement for DEP-1/PTPeta in somatostatin inhibition of cell proliferation in post-surgical specimens derived from different grade human gliomas. Although all of the glioma analyzed expressed somatostatin receptor mRNA, DEP-1/PTPeta expression was limited to 8 of 22 of the tumors. Culturing seven gliomas, a correlation between the expression of DEP-1/PTPeta and the somatostatin antiproliferative effects was identified. In conclusion we propose that the expression and activation of DEP-1/PTPeta is required for somatostatin inhibition of glioma proliferation.
Massa
Alessandro
A
Department of Oncology Biology and Genetics, University of Genova, 16132 Genova, Italy.
Barbieri
Federica
F
Aiello
Cinzia
C
Arena
Sara
S
Pattarozzi
Alessandra
A
Pirani
Paolo
P
Corsaro
Alessandro
A
Iuliano
Rodolfo
R
Fusco
Alfredo
A
Zona
Gianluigi
G
Spaziante
Renato
R
Florio
Tullio
T
Schettini
Gennaro
G
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002455:Cell Division / Q000187:drug effects*; D002460:Cell Line; D004789:Enzyme Activation; D005260:Female; D005910:Glioma / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010641:Phenotype; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*; D013004:Somatostatin / Q000494:pharmacology*; D013223:Statistics as Topic; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
D007527:Isoenzymes; D025521:Tumor Suppressor Proteins; D013004:Somatostatin; D020928:Mitogen-Activated Protein Kinases; D017027:Protein Tyrosine Phosphatases