Somatostatin signaling in pituitary tumor cells
Somatostatin regulates neurotransmission, inhibition of hormone secretion and proliferation, and it is used for the treatment of neuroendocrine tumors. However, there are tumors that cannot benefit from the antiproliferative action of somatostatin analogues, despite the presence of somatostatin receptors. The aim of the present study was to characterize the signaling cascade originating from somatostatin binding, in order to define potential targets responsible for the resistance to somatostatin analogue treatment. We found 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 it is downregulated 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 octreotide’s action. Zac1 was found to be 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 PDK1 and Akt, and activated glycogen synthase kinase 3β (GSK3β). The inhibitory action of octreotide on the members of the PI3K pathway seem to originate from a decrease in phosphatidylinositol (3,4,5)-trisphosphate levels as determined by thin layer chromatography. Therefore, in pituitary tumor cells, somatostatin analogues produce their antiproliferative action by acting on the PI3K/Akt signaling pathway and increasing Zac1 gene expression. Currently we are investigating ways to improve the antiproliferative action of somatostatin analogues by inhibiting members of the PI3K pathway.
Fig. 1 Proposed scheme for the signaling cascade taking place after octreotide treatment in pituitary cells. Giα associates with SSTR2 and SHP-1. After 10 min octreotide treatment, SHP-1 dephosphorylates the PI3K regulatory subunit p85 and inactivates PI3K, without involving PTEN. Three hours later PDK1, AKT and GSK3β are dephosphorylated and GSK3β is activated. This activation results in increase in p53 transcriptional activity and ZAC1 transcription 6 hours after octreotide treatment. Gβγ and SHP-2 were not needed for octreotide’s action in pituitary cells.
Research groups involved:
Marcelo Paez-Pereda, Ph.D., Affectis Pharmaceuticals, Munich, Germany
Uberto Pagotto, M.D., Ph.D., University of Bologna, Italy
Tullio Florio, M.D., University of Genova, Italy
Christophe Erneux, M.D. IRIBHM, Belgium
Mathias Strowski, M.D., Charite, University of Berlin, Germany
Michael Buchfelder, M.D., Dept. of Neurosurgery, University of Erlangen, Germany
Marco Losa, M.D., Instituto San Raffale, Milano, Italy
Theodoropoulou M, Zhang J, Laupheimer S, Paez-Pereda M, Erneux C, Florio T, Pagotto U, Stalla GK (2006) Octreotide, a somatostatin analogue, mediates its antiproliferative action in pituitary tumor cells by altering phosphatidylinositol 3-kinase signaling and inducing Zac1 expression. Cancer Res 66:1576-1582