title: Differential downregulation of telomerase activity by bortezomib in multiple myeloma cells-multiple regulatory pathways in vitro and ex vivo.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Laniado Medical Center, Netanya, Israel.
authors.forename: C
authors.initials: C
authors.lastname: Weiss
authors.forename: O
authors.initials: O
authors.lastname: Uziel
authors.forename: O
authors.initials: O
authors.lastname: Wolach
authors.forename: J
authors.initials: J
authors.lastname: Nordenberg
authors.forename: E
authors.initials: E
authors.lastname: Beery
authors.forename: S
authors.initials: S
authors.lastname: Bulvick
authors.forename: G
authors.initials: G
authors.lastname: Kanfer
authors.forename: O
authors.initials: O
authors.lastname: Cohen
authors.forename: R
authors.initials: R
authors.lastname: Ram
authors.forename: M
authors.initials: M
authors.lastname: Bakhanashvili
authors.forename: H
authors.initials: H
authors.lastname: Magen-Nativ
authors.forename: N
authors.initials: N
authors.lastname: Shilo
authors.forename: M
authors.initials: M
authors.lastname: Lahav
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019175:DNA Methylation; D015536:Down-Regulation; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000201:enzymology; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D051571:Protein Kinase C-alpha / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology*; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib; D051057:Proto-Oncogene Proteins c-akt; C496628:PRKCA protein, human; D051571:Protein Kinase C-alpha; C509186:TERT protein, human; D019098:Telomerase