Differential Downregulation of Telomerase Activity by Bortezomib in Multiple Myeloma Cells- Regulatory Pathways and Clinical Implications.

The proteasome inhibitor bortezomib is an effective drug in Multiple Myeloma (MM). However, its exact mechanism of action is not yet fully understood. The importance of telomerase in the biology and prognosis MM is well established, but its response to bortezomib has not been assessed yet. In light of common signaling pathways of connecting telomerase regulation and bortezomib known mechanisms of action, we surmised that the drug may affect the activity of telomerase in MM cells.

Bortezomib downregulated telomerase activity in all MM cell lines. However, the kinetics of this downregulation varied between the two cell lines examined. Whereas in ARP-1 cells telomerase activity decreased 24 hours after bortezomib treatment, in CAG cells the effect was observed only after 48 hours. These finding imply different regulatory mechanisms between these lines. In both lines bortezomib transcriptionally downregulated telomerase activity by inhibiting hTERT expression. ChIP (Chromatin Immune Precipitation) analysis showed that SP-1 and C-Myc transcription factors mediate this transcriptional downregulation of telomerase. Interestingly, the binding of NFkB to hTERT promoter is enhanced in response to the drug, consistent with a recent study reporting upregulation of NFkB by bortezomib. We are currently looking in depth at the pathways leading to these phenomena. However, the two lines differed in the post translational modification of AKT, which phosphorylates telomerase post-translationally. Whereas in ARP-1 cells the phosphorylated form of AKT is downregulated in response to bortezomib, the drug did not affect AKT phosphorylation in CAG cells. These findings explain the different kinetics of telomerase downregulation and are in keeping with previous data showing different AKT response between these two cell lines.

Our results shed light on the effects and mechanism of bortezomib on telomerase activity in MM. Te differential response of pAKT pathway is in keeping with recent studies suggesting differential dependency of MM cells on pAKT. Telomerase inhibition by bortezomib may be of varying efficacy in subsets of MM patients in relation to their pAKT dependency. A correlation may also be found between the effect of bortezomib on telomerase activity and resistance to bortezomib in MM. As such, the ex vivo assessment of telomerase activity response to treatment may serve as a prognostic feature and add to therapeutic armamentarium by addition of telomerase inhibitors in defined subsets of patients.

No relevant conflicts of interest to declare.