gms | German Medical Science

61st Annual Meeting of the German Society of Neurosurgery (DGNC) as part of the Neurowoche 2010
Joint Meeting with the Brazilian Society of Neurosurgery on the 20 September 2010

German Society of Neurosurgery (DGNC)

21 - 25 September 2010, Mannheim

Downregulation of Wnt/β-catenin pathway in ACTH-secreting pituitary cell line AtT-20 by somatostatin

Meeting Abstract

  • Muhammad Nasir Khan Khattak - Neurochirurgische Klinik, Friedrich-Alexander Universität Erlagen-Nürnberg, Germany
  • Michael Buchfelder - Neurochirurgische Klinik, Friedrich-Alexander Universität Erlagen-Nürnberg, Germany
  • Natalia Kremenevskaya - Neurochirurgische Klinik, Friedrich-Alexander Universität Erlagen-Nürnberg, Germany

Deutsche Gesellschaft für Neurochirurgie. 61. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC) im Rahmen der Neurowoche 2010. Mannheim, 21.-25.09.2010. Düsseldorf: German Medical Science GMS Publishing House; 2010. DocP1763

DOI: 10.3205/10dgnc234, URN: urn:nbn:de:0183-10dgnc2340

Published: September 16, 2010

© 2010 Khattak et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc-nd/3.0/deed.en). You are free: to Share – to copy, distribute and transmit the work, provided the original author and source are credited.


Outline

Text

Objective: The Wnt/β-catenin signalling pathway plays a critical role in normal development as well as in tumorigenesis of various tissues including endocrines. We have shown previously that the Wnt/β-catenin pathway is dysregulated in adrenocorticotropin (ACTH)-secreting pituitary adenomas. In this context, SRIF has been shown to inhibit ACTH secretion and proliferation of an ACTH-secreting pituitary cell line AtT-20. The mechanisms remain largely unclear. The aim of the present study was to investigate the effect of SRIF on the Wnt/ß-catenin pathway in ACTH-secreting pituitary cells.

Methods: The ACTH secreting mouse pituitary cell line AtT-20 was treated with SRIF (3 µM) and its effect on the expression of β-catenin, GSK-3β, TCF-4 and Cyclin D1 was analyzed both at RNA and protein levels by RT-PCR and Western blotting, respectively. The ratio of phospho-β-catenin to total β-catenin and phospho-GSK-3β to total GSK-3β were studied by Western blotting. The nuclear expression of β-catenin was investigated by immunoflourescence.

Results: In the AtT-20 cells, SRIF inhibited basal activation of the Wnt/β-catenin pathway as demonstrated by the decrease of β-catenin, TCF-4 and cyclin D1 expression. SRIF decreased the phosphorylation of GSK-3β at Ser9, increased phosphorylation of β-catenin at Ser33/37 and as a result accelerated degradation of β-catenin. It indicates that SRIF may decelerate Wnt/β-catenin signalling through its action on the phosphorylation status of GSK-3β. We also tested the functional importance of Wnt/β-catenin signalling for the control of AtT-20 cell proliferation. The AtT-20 cells were transfected with dominant-negative TCF-4, that lacks the β-catenin binding domain. The transfection reduced both mRNA and protein expression of cyclin D1 and inhibited cell proliferation, which demonstrates the functional significance of the Wnt/β-catenin pathway for the proliferation of AtT-20 cells. This was further supported by the decrease in β-catenin nuclear expression under SRIF treatment.

Conclusions: Our data demonstrate the important role of e Wnt/β-catenin signalling in proliferation control of pituitary corticotrophs and describe a mechanism for its regulation by SRIF. Inhibition of the Wnt/β-catenin pathway by SRIF or its analogs may be one potential approach to inhibit proliferation and excessive hormone secretion in the ACTH-secreting pituitary cells.