Selective tyrosine kinase inhibitor, STI571, inhibits growth of p53 mutant anaplastic thyroid cancer cells by inducing S–G2 transition arrest

Abstract

A non-receptor-type tyrosine kinase, c-Abl, interacts with the tumor suppressor protein p53 and is critical in the regulation of the cell cycle. To establish a molecular targeting therapy for anaplastic thyroid carcinomas with mutated p53, we studied the therapeutic potential of the c-Abl specific tyrosine kinase inhibitor, STI571. In cell growth assays, FRO (undetectable p53) and ARO (mutated p53) cell lines showed marked inhibition of cell growth after treatment with STI571. In contrast, KTC-1, a papillary thyroid cancer cell line with wild-type p53, showed no suppression of cell growth after treatment with STI571. Furthermore, cell growth was restored in STI571-treated 1F3, a cell line established from FRO by stable transfection with wild-type p53. Cell cycle analysis revealed that STI571 increased the number of cells in S phase and decreased the proportion in G2–M phase in FRO, indicating the induction of S–G2 transition arrest. These changes were accompanied by the increased expression of p21 cip1 and p27 kip1 and reduced expression of cyclin A, B1, and cdc2 in FRO cells treated with STI571. These results demonstrate that the suppression of c-Abl activity by STI571 may be a potential anti-cancer strategy for p53 mutant undifferentiated thyroid carcinomas.