Bortezomib-Resistant Nuclear Factor-κB Activity in Multiple Myeloma Cells
- 1 August 2008
- journal article
- Published by American Association for Cancer Research (AACR) in Molecular Cancer Research
- Vol. 6 (8), 1356-1364
- https://doi.org/10.1158/1541-7786.mcr-08-0108
Abstract
Bortezomib (Velcade/PS341), a proteasome inhibitor used in the treatment of multiple myeloma (MM), can inhibit activation of nuclear factor-κB (NF-κB), a family of transcription factors often deregulated and constitutively activated in primary MM cells. NF-κB can be activated via several distinct mechanisms, including the proteasome inhibitor–resistant (PIR) pathway. It remains unknown what fraction of primary MM cells harbor constitutive NF-κB activity maintained by proteasome-dependent mechanisms. Here, we report an unexpected finding that constitutive NF-κB activity in 10 of 14 primary MM samples analyzed is refractory to inhibition by bortezomib. Moreover, when MM cells were cocultured with MM patient-derived bone marrow stromal cells (BMSC), microenvironment components critical for MM growth and survival, further increases in NF-κB activity were observed that were also refractory to bortezomib. Similarly, MM-BMSCs caused PIR NF-κB activation in the RPMI8226 MM cell line, leading to increased NF-κB–dependent transcription and resistance to bortezomib-induced apoptosis. Our findings show that primary MM cells frequently harbor PIR NF-κB activity that is further enhanced by the presence of patient-derived BMSCs. They also suggest that this activity is likely relevant to the drug resistance development in some patients. Further elucidation of the mechanism of PIR NF-κB regulation could lead to the identification of novel diagnostic biomarkers and/or therapeutic targets for MM treatment. (Mol Cancer Res 2008;6(8):1356–64)Keywords
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This publication has 45 references indexed in Scilit:
- New therapies in multiple myelomaClinical and Experimental Medicine, 2007
- Frequent Engagement of the Classical and Alternative NF-κB Pathways by Diverse Genetic Abnormalities in Multiple MyelomaCancer Cell, 2007
- Promiscuous Mutations Activate the Noncanonical NF-κB Pathway in Multiple MyelomaCancer Cell, 2007
- Integrating cell-signalling pathways with NF-κB and IKK functionNature Reviews Molecular Cell Biology, 2007
- Proteasome inhibitors: antitumor effects and beyondLeukemia, 2006
- Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cellsBlood, 2006
- Nuclear factor-κB in cancer development and progressionNature, 2006
- Evidence for a phosphorylation-independent role for Ser 32 and 36 in proteasome inhibitor-resistant (PIR) IκBα degradation in B cellsExperimental Cell Research, 2005
- A mechanistic insight into a proteasome-independent constitutive inhibitor kappaBalpha (IkappaBalpha) degradation and nuclear factor kappaB (NF-kappaB) activation pathway in WEHI-231 B-cellsBiochemical Journal, 2004
- CK2 Is a C-Terminal IκB Kinase Responsible for NF-κB Activation during the UV ResponseMolecular Cell, 2003