Differential downregulation of telomerase activity by bortezomib in multiple myeloma cells-multiple regulatory pathways in vitro and ex vivo

C. Weiss, O. Uziel, O. Wolach, J. Nordenberg, E. Beery, S. Bulvick, G. Kanfer, O. Cohen, R. Ram, M. Bakhanashvili, H. Magen-Nativ, N. Shilo, M. Lahav

Research output: Contribution to journalArticlepeer-review

Abstract

Background:The importance of telomerase in multiple myeloma (MM) is well established; however, its response to bortezomib has not been addressed.Methods:The effect of bortezomib on telomerase activity and cell proliferation was evaluated in four MM cell lines and in myeloma cells obtained from eight patients. The mechanism of telomerase regulation on epigenetic, transcriptional, and post-translational levels was further assessed in two selected cell lines: ARP-1 and CAG. Clinical data were correlated with the laboratory findings.Results:Bortezomib downregulated telomerase activity and decreased proliferation in all cell lines and cells obtained from patients, albeit in two different patterns of kinetics. ARP-1 cells demonstrated higher and earlier sensitivity than CAG cells due to differential phosphorylation of hTERT by PKCα. Methylation of hTERT promoter was not affected. Transcription of hTERT was similarly inhibited in both lines by decreased binding of SP-1 and not of C-Myc and NFκB. The ex vivo results confirmed the in vitro findings and suggested existence of clinical relevance.Conclusion: Bortezomib downregulates telomerase activity in MM cells both transcriptionally and post-translationally. MM cells, both in vitro and in patients, exhibit different sensitivity to the drug due to different post-translational response. The effect of bortezomib on telomerase activity may correlate with resistance to bortezomib in patients, suggesting its potential utility as a pre-treatment assessment.

Original languageEnglish
Pages (from-to)1844-1852
Number of pages9
JournalBritish Journal of Cancer
Volume107
Issue number11
DOIs
StatePublished - 20 Nov 2012

Keywords

  • bortezomib
  • multiple myeloma
  • telomerase
  • telomerase regulation
  • telomere

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