This Article Full Text Full Text (PDF) A retraction has been published Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rao, A. S. Articles by Brabant, G. Search for Related Content PubMed PubMed Citation Articles by Rao, A. S. Articles by Brabant, G. Related Collections Thyroid Endocrine Oncology

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

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.

This article has been cited by other articles:

				R. C Smallridge, L. A Marlow, and J. A Copland Anaplastic thyroid cancer: molecular pathogenesis and emerging therapies Endocr. Relat. Cancer, March 1, 2009; 16(1): 17 - 44. [Abstract] [Full Text] [PDF]

				L. Miele, N. Takebe, and S. P. Ivy The Cancer Stem Cell Hypothesis, Embryonic Signaling Pathways, and Therapeutics: Targeting an Elusive Concept ASCO Educational Book, January 1, 2009; 2009(1): 145 - 156. [Abstract] [Full Text] [PDF]