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/-catenin cascade and is able to modulate the pathway.

Objective: Conflicting data are reported on the therapeutic effects of imatinib in anaplastic thyroid carcinomas but the molecular mechanism of action is unclear. Here we further delineated the anti-tumor effects and the potential efficacy of imatinib in dedifferentiated thyroid carcinomas.

Results: Tissue microarray of histologically proven anaplastic thyroid carcinomas (ATC) (n = 12) demonstrated that 6/12 tumors expressed at least one of the imatinib sensitive TKs. Similarily, imatinib sensitive TKs were detected in 7/10 thyroid cancer cell lines derived from metastatic papillary, follicular and ATCs. Co-immunoprecipation in ARO cells demonstrated a direct link between c-abl and -catenin. Imatinib (10 µM for 48 h) drastically reduced -catenin expression and redistributed it from the nucleus to the cell membrane. It stabilized adherens junctions by increasing -catenin/E-Cadherin binding and reduced the invasive potential of thyroid cancer. Furthermore, imatinib (10 µM for 48 h) attenuated TCF/LEF activity, reduced cyclinD1 levels and dose-dependently suppressed thyrocyte proliferation by half without affecting apoptosis.

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