Bortezomib-resistant nuclear factor-κB activity in multiple myeloma cells

Stephanie Markovina, Natalie S. Callander, Shelby L. O'Connor, Jihoon Kim, Jae E. Werndli, Martha Raschko, Catherine P. Leith, Brad S. Kahl, Kyung Mann Kim, Shigeki Miyamoto

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108 Scopus citations

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.

Original languageEnglish
Pages (from-to)1356-1364
Number of pages9
JournalMolecular Cancer Research
Volume6
Issue number8
DOIs
StatePublished - Aug 1 2008
Externally publishedYes

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    Markovina, S., Callander, N. S., O'Connor, S. L., Kim, J., Werndli, J. E., Raschko, M., Leith, C. P., Kahl, B. S., Kim, K. M., & Miyamoto, S. (2008). Bortezomib-resistant nuclear factor-κB activity in multiple myeloma cells. Molecular Cancer Research, 6(8), 1356-1364. https://doi.org/10.1158/1541-7786.MCR-08-0108