Gene expression analysis of B-lymphoma cells resistant and sensitive to bortezomib

Reshma Shringarpure, Laurence Catley, Deepak Bhole, Renate Burger, Klaus Podar, Yu-Tzu Tai, Benedikt Kessler, Paul Galardy, Hidde Ploegh, Pierfrancesco Tassone, Teru Hideshima, Constantine Mitsiades, Nikhil C Munshi, Dharminder Chauhan, Kenneth C Anderson

Research output: Journal article (peer-reviewed)Journal article

90 Citations (Scopus)

Abstract

The proteasome inhibitor bortezomib has shown impressive clinical activity alone and in combination with conventional and other novel agents for the treatment of multiple myeloma (MM). Although bortezomib is known to be a selective proteasome inhibitor, the downstream mechanisms of cytotoxicity and drug resistance are poorly understood. However, resistance to bortezomib as a single agent develops in the majority of patients, and activity in other malignancies has been less impressive. To elucidate mechanisms of bortezomib resistance, we compared differential gene expression profiles of bortezomib-resistant SUDHL-4 and bortezomib-sensitive SUDHL-6 diffuse large B-cell lymphoma lines in response to bortezomib. At concentrations that effectively inhibited proteasome activity, bortezomib induced apoptosis in SUDHL-6 cells, but not in SUDHL-4 cells. We showed that overexpression of activating transcription factor 3 (ATF3), ATF4, ATF5, c-Jun, JunD and caspase-3 is associated with sensitivity to bortezomib-induced apoptosis, whereas overexpression of heat shock protein (HSP)27, HSP70, HSP90 and T-cell factor 4 is associated with bortezomib resistance.

Original languageEnglish
Pages (from-to)145-156
Number of pages12
JournalBritish Journal of Haematology
Volume134
Issue number2
DOIs
Publication statusPublished - Jul 2006
Externally publishedYes

Keywords

  • Antineoplastic Agents/pharmacology
  • Apoptosis/drug effects
  • Boronic Acids/pharmacology
  • Bortezomib
  • Caspase 3
  • Caspases/metabolism
  • Cell Proliferation/drug effects
  • Cell Survival/drug effects
  • Dose-Response Relationship, Drug
  • Drug Resistance, Neoplasm/genetics
  • Gene Expression Profiling/methods
  • Humans
  • Lymphoma, B-Cell/genetics
  • Lymphoma, Large B-Cell, Diffuse/genetics
  • Polymerase Chain Reaction/methods
  • Proteasome Inhibitors
  • Pyrazines/pharmacology
  • TCF Transcription Factors/biosynthesis
  • Transcription Factor 7-Like 2 Protein
  • Tumor Cells, Cultured

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