title: Gene expression analysis of B-lymphoma cells resistant and sensitive to bortezomib.
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.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Reshma
authors.initials: R
authors.lastname: Shringarpure
authors.forename: Laurence
authors.initials: L
authors.lastname: Catley
authors.forename: Deepak
authors.initials: D
authors.lastname: Bhole
authors.forename: Renate
authors.initials: R
authors.lastname: Burger
authors.forename: Klaus
authors.initials: K
authors.lastname: Podar
authors.forename: Yu-Tzu
authors.initials: YT
authors.lastname: Tai
authors.forename: Benedikt
authors.initials: B
authors.lastname: Kessler
authors.forename: Paul
authors.initials: P
authors.lastname: Galardy
authors.forename: Hidde
authors.initials: H
authors.lastname: Ploegh
authors.forename: Pierfrancesco
authors.initials: P
authors.lastname: Tassone
authors.forename: Teru
authors.initials: T
authors.lastname: Hideshima
authors.forename: Constantine
authors.initials: C
authors.lastname: Mitsiades
authors.forename: Nikhil C
authors.initials: NC
authors.lastname: Munshi
authors.forename: Dharminder
authors.initials: D
authors.lastname: Chauhan
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016133:Polymerase Chain Reaction / Q000379:methods; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000494:pharmacology*; D051820:TCF Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D058118:Transcription Factor 7-Like 2 Protein; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D061988:Proteasome Inhibitors; D011719:Pyrazines; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; D000069286:Bortezomib; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases