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

• Published in: British journal of cancer Vol. 107; no. 11; pp. 1844 - 1852
• Main Authors: Weiss, C, Uziel, O, Wolach, O, Nordenberg, J, Beery, E, Bulvick, S, Kanfer, G, Cohen, O, Ram, R, Bakhanashvili, M, Magen-Nativ, H, Shilo, N, Lahav, M
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 20.11.2012; Nature Publishing Group
• Subjects: 692/699/67/1990/804; 692/700/565/1436; Angiogenesis; Antineoplastic Agents - pharmacology; Apoptosis; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Bone marrow; Boronic Acids - pharmacology; Bortezomib; Cancer Research; Cell cycle; Cell Line, Tumor; Cell Survival - drug effects; DNA Methylation; Down-Regulation; Drug Resistance; Epidemiology; Humans; Immunodeficiencies. Immunoglobulinopathies; Immunoglobulinopathies; Immunopathology; Medical prognosis; Medical research; Medical sciences; Molecular Medicine; Multiple myeloma; Multiple Myeloma - drug therapy; Multiple Myeloma - enzymology; Oncology; Penicillin; Phosphorylation; Promoter Regions, Genetic; Protein Kinase C-alpha - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Pyrazines - pharmacology; Telomerase; Telomerase - antagonists & inhibitors; Telomerase - genetics; Translational Therapeutics; Tumors; Tel Aviv Israel; Israel; multiple myeloma; telomerase; telomerase regulation; bortezomib; telomere; Antineoplastic agent; Immunopathology; Bortezomib; Enzyme; Malignant hemopathy; Myeloma; In vitro; Telomere; Biological activity; In vivo; Cancerology; Immunoglobulinopathy; Ex vivo; Analog; Proteasome inhibitor; Lymphoproliferative syndrome; Dipeptides; Telomerase; Regulatory cell; Cancer
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2012.460

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 PKC α . 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 NF κ B. 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.