title: 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.
authors.affiliation: Felsenstein Medical Research Center, Beilinson Hospital, Sackler School of Medicine, Tel Aviv University, Israel.
authors.forename: Saar
authors.initials: S
authors.lastname: Shapira
authors.forename: Galit
authors.initials: G
authors.lastname: Granot
authors.forename: Rahav
authors.initials: R
authors.lastname: Mor-Tzuntz
authors.forename: Pia
authors.initials: P
authors.lastname: Raanani
authors.forename: Orit
authors.initials: O
authors.lastname: Uziel
authors.forename: Meir
authors.initials: M
authors.lastname: Lahav
authors.forename: Ofer
authors.initials: O
authors.lastname: Shpilberg
mesh_terms: D000069439:Dasatinib; D006801:Humans; D020014:K562 Cells; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000494:pharmacology*; D019098:Telomerase / Q000037:antagonists & inhibitors*; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D011505:Protein-Tyrosine Kinases; D019098:Telomerase; C498826:nilotinib; D000069439:Dasatinib