The Effect of Imatinib Mesylate on the Signal Transduction Cascade Leading to down Regulation of Telomerase Activity in K562 Cells.
Authors: Mor Rahav , Uziel Orit , Shpilberg Ofer , Lahav Judith , Raanani Pia , Rabizadeh Esther , Lahav Meir , Granot Galit 
Published: October 2019

Imatinib mesylate (IM) is a tyrosine kinase inhibitor selective for Bcr-Abl, c-Kit, and platelet-derived growth factor receptor kinases. IM inhibits kinase activity through competition for ATP binding. IM is indicated for the treatment of newly diagnosed patients with Philadelphia chromosome positive (BCR-ABL positive) chronic myeloid leukemia (CML) in chronic phase. Recent publications demonstrate that this drug may also target other cellular components. In light of the important role of telomerase in malignant transformation, we evaluated the effect of IM on the signal transduction cascade leading to modulation of telomerase activity in the BCR-ABL positive K562 cell-line. In addition, we studied the effect of IM on telomerase in an IM resistant K562 cell-line (K562res). The K562res cell-line is resistant to the effect of IM on the BCR-ABL protein. However, the effect of IM on telomerase in these cells is unknown. Therefore, using these cells will enable us to study the connection between the signal transduction cascade of BCR-ABL and that of telomerase.

IM caused an 80% inhibition of telomerase activity in both K562 and K562res cell-lines. Inhibition of telomerase activity was associated with 50% inhibition of proliferation. Inhibition of telomerase activity was not caused by changes in the transcription level of hTERT (the catalytic subunit of the enzyme). On the other hand, it seemed mainly to be caused by post-translational modifications only in K562 cells namely, a 2-fold dephosphorylation of AKT, known to phosphorylate telomerase. In addition, IM was found to upregulate the expression of PTEN (known to negatively regulate AKT) again only in K562 cells. IM did not affect the levels of phosphorylaetd AKT or PTEN in K562res cells. However, IM caused an approximate 2-fold upregulation of p53 (a transcription factor of PTEN) levels both in K562 and K562res cells.

Our results demonstrate the ability of IM to inhibit telomerase activity in BCR-ABL expressing cell lines. Telomerase activity inhibition was demonstrated in K562 cells as well as in K562 cells resistant to high concentrations of IM. Therefore, the inhibitory effect of IM on telomerase activity isn’t necessarily mediated through the known tyrosine kinase targets of IM. The effect of IM on the signal transduction cascade leading to the down-regulation of telomerase activity seems to be different in K562 cells and K562res cells. While the signal transduction cascade in K562 cells appears to go through AKT and PTEN, the response to IM in K562res cells seems to be mediated by other yet unknown pathways. Future work is needed in order to clarify possible mechanism(s) by which IM down-regulates telomerase activity in these cells.

This study supports previous studies demonstrating telomerase activity as an additional cellular target of IM. In addition, this study shows that cells known to be resistant to IM with regards to its effect on BCR-ABL could still be sensitive to IM treatment regarding other cellular components.