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

doi:10.1111/j.1365-2141.2006.06132.x

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

91 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 language	English
Pages (from-to)	145-156
Number of pages	12
Journal	British Journal of Haematology
Volume	134
Issue number	2
DOIs	https://doi.org/10.1111/j.1365-2141.2006.06132.x
Publication status	Published - Jul 2006
Externally published	Yes

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

Access to Document

10.1111/j.1365-2141.2006.06132.x

Cite this

Shringarpure, R., Catley, L., Bhole, D., Burger, R., Podar, K., Tai, Y.-T., Kessler, B., Galardy, P., Ploegh, H., Tassone, P., Hideshima, T., Mitsiades, C., Munshi, N. C., Chauhan, D., & Anderson, K. C. (2006). Gene expression analysis of B-lymphoma cells resistant and sensitive to bortezomib. British Journal of Haematology, 134(2), 145-156. https://doi.org/10.1111/j.1365-2141.2006.06132.x

@article{e4812816bcff4313917073fbd3347300,

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.",

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",

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

year = "2006",

month = jul,

doi = "10.1111/j.1365-2141.2006.06132.x",

language = "English",

volume = "134",

pages = "145--156",

journal = "British Journal of Haematology",

issn = "0007-1048",

publisher = "John Wiley and Sons Inc.",

number = "2",

}

Shringarpure, R, Catley, L, Bhole, D, Burger, R, Podar, K, Tai, Y-T, Kessler, B, Galardy, P, Ploegh, H, Tassone, P, Hideshima, T, Mitsiades, C, Munshi, NC, Chauhan, D & Anderson, KC 2006, 'Gene expression analysis of B-lymphoma cells resistant and sensitive to bortezomib', British Journal of Haematology, vol. 134, no. 2, pp. 145-156. https://doi.org/10.1111/j.1365-2141.2006.06132.x

TY - JOUR

T1 - Gene expression analysis of B-lymphoma cells resistant and sensitive to bortezomib

AU - Shringarpure, Reshma

AU - Catley, Laurence

AU - Bhole, Deepak

AU - Burger, Renate

AU - Podar, Klaus

AU - Tai, Yu-Tzu

AU - Kessler, Benedikt

AU - Galardy, Paul

AU - Ploegh, Hidde

AU - Tassone, Pierfrancesco

AU - Hideshima, Teru

AU - Mitsiades, Constantine

AU - Munshi, Nikhil C

AU - Chauhan, Dharminder

AU - Anderson, Kenneth C

PY - 2006/7

Y1 - 2006/7

N2 - 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.

AB - 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.

KW - Antineoplastic Agents/pharmacology

KW - Apoptosis/drug effects

KW - Boronic Acids/pharmacology

KW - Bortezomib

KW - Caspase 3

KW - Caspases/metabolism

KW - Cell Proliferation/drug effects

KW - Cell Survival/drug effects

KW - Dose-Response Relationship, Drug

KW - Drug Resistance, Neoplasm/genetics

KW - Gene Expression Profiling/methods

KW - Humans

KW - Lymphoma, B-Cell/genetics

KW - Lymphoma, Large B-Cell, Diffuse/genetics

KW - Polymerase Chain Reaction/methods

KW - Proteasome Inhibitors

KW - Pyrazines/pharmacology

KW - TCF Transcription Factors/biosynthesis

KW - Transcription Factor 7-Like 2 Protein

KW - Tumor Cells, Cultured

UR - http://www.scopus.com/inward/record.url?scp=33745169658&partnerID=8YFLogxK

U2 - 10.1111/j.1365-2141.2006.06132.x

DO - 10.1111/j.1365-2141.2006.06132.x

M3 - Journal article

C2 - 16846475

SN - 0007-1048

VL - 134

SP - 145

EP - 156

JO - British Journal of Haematology

JF - British Journal of Haematology

IS - 2

ER -

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

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Cite this