title: The expression of the phosphotyrosine phosphatase DEP-1/PTPeta dictates the responsivity of glioma cells to somatostatin inhibition of cell proliferation.
abstract: 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.
authors.affiliation: Department of Oncology Biology and Genetics, University of Genova, 16132 Genova, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Massa
authors.forename: Federica
authors.initials: F
authors.lastname: Barbieri
authors.forename: Cinzia
authors.initials: C
authors.lastname: Aiello
authors.forename: Sara
authors.initials: S
authors.lastname: Arena
authors.forename: Alessandra
authors.initials: A
authors.lastname: Pattarozzi
authors.forename: Paolo
authors.initials: P
authors.lastname: Pirani
authors.forename: Alessandro
authors.initials: A
authors.lastname: Corsaro
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Iuliano
authors.forename: Alfredo
authors.initials: A
authors.lastname: Fusco
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Zona
authors.forename: Renato
authors.initials: R
authors.lastname: Spaziante
authors.forename: Tullio
authors.initials: T
authors.lastname: Florio
authors.forename: Gennaro
authors.initials: G
authors.lastname: Schettini
mesh_terms: 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*
chemical_list: D007527:Isoenzymes; D025521:Tumor Suppressor Proteins; D013004:Somatostatin; D020928:Mitogen-Activated Protein Kinases; D017027:Protein Tyrosine Phosphatases