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

• Published in: Molecular cancer research 2008-08, Vol.6 (8), p.1356-1364
• Main Authors: Markovina, Stephanie, Callander, Natalie S, O'Connor, Shelby L, Kim, Jihoon, Werndli, Jae E, Raschko, Martha, Leith, Catherine P, Kahl, Brad S, Kim, Kyungmann, Miyamoto, Shigeki
• Format: Article
• Language: English
• Subjects: Apoptosis - drug effects; Bone Marrow Cells - drug effects; Bone Marrow Cells - pathology; Boronic Acids - pharmacology; Bortezomib; Cell Line, Tumor; Drug Resistance, Neoplasm - drug effects; Enzyme Inhibitors - pharmacology; Genes, Reporter; Green Fluorescent Proteins - metabolism; Humans; Multiple Myeloma - metabolism; Multiple Myeloma - pathology; NF-kappa B - metabolism; Proteasome Inhibitors; Pyrazines - pharmacology; Stromal Cells - drug effects; Stromal Cells - pathology
• ISSN: 1541-7786
• DOI: 10.1158/1541-7786.MCR-08-0108

Bortezomib (Velcade/PS341), a proteasome inhibitor used in the treatment of multiple myeloma (MM), can inhibit activation of nuclear factor-kappaB (NF-kappaB), a family of transcription factors often deregulated and constitutively activated in primary MM cells. NF-kappaB 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-kappaB activity maintained by proteasome-dependent mechanisms. Here, we report an unexpected finding that constitutive NF-kappaB 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-kappaB activity were observed that were also refractory to bortezomib. Similarly, MM-BMSCs caused PIR NF-kappaB activation in the RPMI8226 MM cell line, leading to increased NF-kappaB-dependent transcription and resistance to bortezomib-induced apoptosis. Our findings show that primary MM cells frequently harbor PIR NF-kappaB 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-kappaB regulation could lead to the identification of novel diagnostic biomarkers and/or therapeutic targets for MM treatment.