These authors contributed equally.
Gene expression analysis of B-lymphoma cells resistant and sensitive to bortezomib*
Article first published online: 26 MAY 2006
British Journal of Haematology
Volume 134, Issue 2, pages 145–156, July 2006
How to Cite
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. and Anderson, K. C. (2006), Gene expression analysis of B-lymphoma cells resistant and sensitive to bortezomib. British Journal of Haematology, 134: 145–156. doi: 10.1111/j.1365-2141.2006.06132.x
Supported by a Fellow's Award (R.S.) and Senior Research Awards (B.K. and K.P.) from the Multiple Myeloma Research Foundation, National Institutes of Health grants P50 CA100707 and PO-1 78378, and the Doris Duke Distinguished Clinical Research Scientist Award (K.C.A.).
- Issue published online: 16 JUN 2006
- Article first published online: 26 MAY 2006
- Received 20 January 2006; accepted for publication 12 April 2006
- proteasome inhibition;
- drug resistance;
- B-cell lymphoma
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.