Second-generation tyrosine kinase inhibitors reduce telomerase activity in K562 cells

Abstract

In this study we present the effects of nilotinib and dasatinib on telomerase activity and regulation. Nilotinib and dasatinib strongly reduced telomerase activity in BCR-ABL-positive (K562) and BCR-ABL-negative (HL60) cells, demonstrating that their effect on telomerase activity is uncoupled from their effect on BCR-ABL. Nilotinib and dasatinib caused a substantial decrease in hTERT mRNA expression. Phospho-Sp1 regulates hTERT transcription. We detected a considerable decrease in Sp1 nuclear expression and binding to the hTERT promoter following exposure to the drugs. We also detected a reduction in Map kinase, known to phosphorylate Sp1. Telomerase is also activated and translocated to the nucleus when phosphorylated by AKT. We detected a decrease in phospho-AKT and a reduction in the nuclear expression of hTERT following exposure to nilotinib and dasatinib. In conclusion, we provide evidence for transcriptional and post-translational inhibition of telomerase by nilotinib and dasatinib which is not necessarily mediated via known targets of these tyrosine kinase inhibitors.