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Octreotide, a Somatostatin Analogue, Mediates Its Antiproliferative Action in Pituitary Tumor Cells by Altering Phosphatidylinositol 3-Kinase Signaling and Inducing Zac1 Expression

¹ Department of Endocrinology, Max Planck Institute of Psychiatry, Munich, Germany; ² Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Free University of Brussels, Brussels, Belgium; ³ Department of Oncology, Biology and Genetics, University of Genova, Genova, Italy; and ⁴ Endocrine Unit, Department of Internal Medicine and Gastroenterology and Center for Applied Biomedical Research, S. Orsola-Malpighi General Hospital, Bologna, Italy

Requests for reprints: Marily Theodoropoulou, Department of Endocrinology, Max Planck Institute of Psychiatry, Kraepelinstrasse 10, D-80804 Munich, Germany. Phone: 0049-89-30622292; Fax: 0049-89-30622605; E-mail: marily{at}mpipsykl.mpg.de.

Somatostatin limits cell growth by inhibiting the proliferative activity of growth factor receptors. In this study, it is shown that in pituitary tumor cells, the somatostatin analogue octreotide produces its antiproliferative action by inducing the expression the tumor suppressor gene Zac1. ZAC/Zac1 induces cell cycle arrest and apoptosis and is highly expressed in normal pituitary, mammary, and ovarian glands but is down-regulated in pituitary, breast, and ovarian tumors. Knocking down Zac1 by RNA interference abolished the antiproliferative effect of octreotide in pituitary tumor cells, indicating that Zac1 is necessary for the action of octreotide. The effect of octreotide on Zac1 expression was pertussis toxin sensitive and was abolished after transfection with a dominant negative vector for SHP-1. Zac1 is a target of the phosphatidylinositol 3-kinase (PI3K) survival pathway. Octreotide treatment decreased the tyrosine phosphorylation levels of the PI3K regulatory subunit p85, induced dephosphorylation of phosphoinositide-dependent kinase 1 (PDK1) and Akt, and activated glycogen synthase kinase 3ß (GSKß). Therefore, in pituitary tumor cells, somatostatin analogues produce their antiproliferative action by acting on the PI3K/Akt signaling pathway and increasing Zac1 gene expression. (Cancer Res 2006; 66(3): 1576-82)

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