Wnt/beta-catenin signaling mediates antineoplastic effects of imatinib mesylate (gleevec) in anaplastic thyroid cancer.
BACKGROUND
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/beta-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 beta-catenin. Imatinib (10 microM for 48 h) drastically reduced beta-catenin expression and redistributed it from the nucleus to the cell membrane. It stabilized adherens junctions by increasing beta-catenin/E-cadherin binding and reduced the invasive potential of thyroid cancer. Furthermore, imatinib (10 microM 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.


CONCLUSIONS
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.
Rao
Annavarapu Srinivas
AS
Department of Gastroenterology, Hepatology, and Endocrinology, D-30625 Hannover, Germany.
Kremenevskaja
Natalia
N
von Wasielewski
Reinhard
R
Jakubcakova
Vladimira
V
Kant
Shashi
S
Resch
Julia
J
Brabant
Georg
G
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D015153:Blotting, Western; D002277:Carcinoma / Q000188:drug therapy* / Q000473:pathology*; D053148:Caspase 3; D053179:Caspase 7; D020169:Caspases / Q000378:metabolism; D049109:Cell Proliferation; D003094:Collagen; D004338:Drug Combinations; D005455:Fluorescent Antibody Technique; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D000068877:Imatinib Mesylate; D047468:Immunoprecipitation; D007797:Laminin; D008156:Luciferases / Q000235:genetics; D018613:Microscopy, Confocal; D020411:Oligonucleotide Array Sequence Analysis; D010879:Piperazines / Q000627:therapeutic use*; D011509:Proteoglycans; D011743:Pyrimidines / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects*; D013778:Tetrazolium Salts; D013844:Thiazoles; D013936:Thymidine / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D014162:Transfection; D014407:Tumor Cells, Cultured; D051176:beta Catenin / Q000502:physiology*
D000970:Antineoplastic Agents; D001549:Benzamides; D004338:Drug Combinations; D007797:Laminin; D010879:Piperazines; D011509:Proteoglycans; D011743:Pyrimidines; D013778:Tetrazolium Salts; D013844:Thiazoles; D051176:beta Catenin; C059485:matrigel; D000068877:Imatinib Mesylate; D003094:Collagen; D008156:Luciferases; C505407:CASP3 protein, human; C505520:CASP7 protein, human; D053148:Caspase 3; D053179:Caspase 7; D020169:Caspases; C022616:thiazolyl blue; D013936:Thymidine