Gene expression analysis of B-lymphoma cells resistant and sensitive to bortezomib.
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.
Shringarpure
Reshma
R
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Catley
Laurence
L
Bhole
Deepak
D
Burger
Renate
R
Podar
Klaus
K
Tai
Yu-Tzu
YT
Kessler
Benedikt
B
Galardy
Paul
P
Ploegh
Hidde
H
Tassone
Pierfrancesco
P
Hideshima
Teru
T
Mitsiades
Constantine
C
Munshi
Nikhil C
NC
Chauhan
Dharminder
D
Anderson
Kenneth C
KC
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
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