The proteasome inhibitor bortezomib disrupts tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expression and natural killer (NK) cell killing of TRAIL receptor-positive multiple myeloma cells.
Bortezomib, a potent 26S proteasome inhibitor, is approved for the treatment of multiple myeloma (MM) and clinical trials are under way to evaluate its efficacy in other malignant diseases. However, cytotoxic effects of bortezomib on immune-competent cells have also been observed. In this study, we show that bortezomib downregulates cell surface expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on primary human interleukin (IL)-2-activated natural killer (NK) cells. Pharmacological inhibition of the transcription factor, NF-kappaB also profoundly decreased TRAIL expression, suggesting that NF-kappaB is involved in the regulation of TRAIL expression in activated human NK cells. Furthermore, perforin-independent killing of the human MM cell lines RPMI8226 and U266 by NK cells was markedly suppressed following bortezomib treatment. In addition, blocking cell surface-bound TRAIL with a TRAIL antibody impaired NK cell-mediated lysis of the TRAIL-sensitive MM cell line, RPMI8226. In conclusion, the proteasome is likely to be involved in the regulation of TRAIL expression in primary human IL-2-activated NK cells. Proteasome inhibition by bortezomib disrupts TRAIL expression and TRAIL dependent and/or independent pathway-mediated killing of myeloma cells, suggesting that bortezomib may potentially hamper NK-dependent immunosurveillance against tumors in patients treated with this drug.
Feng
Xiaoli
X
Division of Molecular Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
Yan
Jie
J
Wang
Yibiao
Y
Zierath
Juleen R
JR
Nordenskjöld
Magnus
M
Henter
Jan-Inge
JI
Fadeel
Bengt
B
Zheng
Chengyun
C
D000328:Adult; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D001483:Base Sequence; D001897:Boronic Acids / Q000009:adverse effects*; D000069286:Bortezomib; D015550:Cell Degranulation / Q000187:drug effects / Q000276:immunology; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D017931:DNA Primers / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007376:Interleukin-2 / Q000494:pharmacology; D020014:K562 Cells; D015979:Killer Cells, Lymphokine-Activated / Q000187:drug effects / Q000276:immunology; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology*; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000276:immunology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D011480:Protease Inhibitors / Q000009:adverse effects*; D011719:Pyrazines / Q000009:adverse effects*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*
D001897:Boronic Acids; D017931:DNA Primers; D007376:Interleukin-2; D016328:NF-kappa B; D011480:Protease Inhibitors; D011719:Pyrazines; D012333:RNA, Messenger; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D000069286:Bortezomib