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J. Biol. Chem., Vol. 279, Issue 28, 29004-29012, July 9, 2004

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The Expression of the Phosphotyrosine Phosphatase DEP-1/PTP Dictates the Responsivity of Glioma Cells to Somatostatin Inhibition of Cell Proliferation^*

Alessandro Massa, Federica Barbieri, Cinzia Aiello, Sara Arena, Alessandra Pattarozzi, Paolo Pirani, Alessandro Corsaro, Rodolfo Iuliano¶, Alfredo Fusco||, Gianluigi Zona**, Renato Spaziante**, Tullio Florio, and Gennaro Schettini

From the Section of Pharmacology, Department of Oncology Biology and Genetics, University of Genova, 16132 Genova, Italy, the Pharmacology and Neuroscience, National Institute for Cancer Research, 16132 Genova, Italy, the ^¶Department of Clinical and Experimental Medicine, University of Catanzaro, 88100 Catanzaro, Italy, the ^||Endocrinology and Experimental Oncology Center, National Research Council and Department of Molecular and Cellular Pathology, University Federico II, 80131 Napoli, Italy, and the ^**Division of Neurosurgery, Department of Neuroscience, Ophthalmology and Genetics, University of Genova, 16132 Genova, Italy

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/PTP, identified in C6 and U87MG cells, in which somatostatin inhibited cell growth. The expression of a dominant negative mutant of DEP-1/PTP in C6 cells abolished somatostatin effects, confirming the involvement of this phosphotyrosine phosphatase in such effects. Somatostatin treatment increased the activity of DEP-1/PTP 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 PTP was able to interact and dephosphorylate ERK1/2 activated by basic fibroblast growth factor. Furthermore, by transfecting PTP in the somatostatin-unresponsive, DEP-1/PTP-deficient U373MG cells, the somatostatin-dependent control of cell proliferation was recovered. Finally we evaluated the requirement for DEP-1/PTP 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/PTP expression was limited to 8 of 22 of the tumors. Culturing seven gliomas, a correlation between the expression of DEP-1/PTP and the somatostatin antiproliferative effects was identified. In conclusion we propose that the expression and activation of DEP-1/PTP is required for somatostatin inhibition of glioma proliferation.

Received for publication, March 31, 2004

^* This work was supported by grants from the Italian Association for Cancer Research and European Union Contract QRTL-1999-00908 (to G. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

These authors contributed equally to this work.

To whom correspondence should be addressed: Section of Pharmacology, Dept. of Oncology, Biology and Genetics, University of Genova, Largo R. Benzi, 10, 16132 Genova, Italy. Tel.: 39-010-5737255; Fax: 39-010-5737257; E-mail: florio{at}cba.unige.it.

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