Bortezomib-resistant nuclear factor-kappaB activity in multiple myeloma cells.
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.
Markovina
Stephanie
S
Department of Pharmacology, University of Wisconsin, Madison, WI 53706, USA.
Callander
Natalie S
NS
O'Connor
Shelby L
SL
Kim
Jihoon
J
Werndli
Jae E
JE
Raschko
Martha
M
Leith
Catherine P
CP
Kahl
Brad S
BS
Kim
Kyungmann
K
Miyamoto
Shigeki
S
D017209:Apoptosis / Q000187:drug effects; D001854:Bone Marrow Cells / Q000187:drug effects / Q000473:pathology; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D009101:Multiple Myeloma / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism*; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000494:pharmacology*; D017154:Stromal Cells / Q000187:drug effects / Q000473:pathology
D001897:Boronic Acids; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D061988:Proteasome Inhibitors; D011719:Pyrazines; D049452:Green Fluorescent Proteins; D000069286:Bortezomib