help button home button Endocrine Society JCEM JCEM Call for Nominations for EIC
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2005-1381
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow A retraction has been published
Right arrow All Versions of this Article:
91/1/159    most recent
Author Manuscript (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Rao, A. S.
Right arrow Articles by Brabant, G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Rao, A. S.
Right arrow Articles by Brabant, G.
Related Collections
Right arrow Endocrine Oncology
Right arrow Thyroid
The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 1 159-168
Copyright © 2006 by The Endocrine Society

Wnt/ß-Catenin Signaling Mediates Antineoplastic Effects of Imatinib Mesylate (Gleevec) in Anaplastic Thyroid Cancer

Annavarapu Srinivas Rao, Natalia Kremenevskaja, Reinhard von Wasielewski, Vladimira Jakubcakova, Shashi Kant, Julia Resch and Georg Brabant

Departments of Gastroenterology, Hepatology, and Endocrinology (A.S.R., N.K., J.R., G.B.) and Pathology (R.v.W.), Institute of Biochemistry (S.K.), Medical School Hannover, and Max-Planck Institute for Experimental Endocrinology (V.J.), D-30625 Hannover, Germany

Address all correspondence and requests for reprints to: Prof. G. Brabant, Department of Gastroenterology, Hepatology, and Endocrinology, Medizinische Hochschule Hannover, Carl-Neuberg Strasse 1, D-30625 Hannover, Germany. E-mail: brabant.georg{at}mh-hannover.de.

Context: Dysregulation of Wnt signaling is a key step in neoplastic thyrocyte proliferation. However, it is unclear whether the selective tyrosine kinase (TK) inhibitor, imatinib mesylate, is linked to the Wnt/ß-catenin cascade and is able to modulate the pathway.

Objective: Conflicting data are reported on the therapeutic effects of imatinib in anaplastic thyroid carcinomas (ATCs), but the molecular mechanism of action is unclear. Here, we further delineated the antitumor effects and the potential efficacy of imatinib in dedifferentiated thyroid carcinomas.

Results: Tissue microarray of histologically proven ATCs (n = 12) demonstrated that six of 12 tumors expressed at least one of the imatinib-sensitive TKs. Similarily, imatinib-sensitive TKs were detected in seven of 10 thyroid cancer cell lines derived from metastatic papillary, follicular, and ATCs. Coimmunoprecipitation in ARO cells demonstrated a direct link between c-abl and ß-catenin. Imatinib (10 µM for 48 h) drastically reduced ß-catenin expression and redistributed it from the nucleus to the cell membrane. It stabilized adherens junctions by increasing ß-catenin/E-cadherin binding and reduced the invasive potential of thyroid cancer. Furthermore, imatinib (10 µM for 48 h) attenuated T cell factor/lymphoid enhancer factor activity, reduced cyclin D1 levels and dose-dependently suppressed thyrocyte proliferation by half without affecting apoptosis.

Conclusion: Our data provide a molecular mechanism for the antitumor activity of imatinib that may help to develop it as a therapeutic option in a subset of ATC patients.






HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals
Copyright © 2006 by The Endocrine Society