Proteasome inhibitor-adapted myeloma cells are largely independent from proteasome activity and show complex proteomic changes, in particular in redox and energy metabolism.
Adaptive resistance of myeloma to proteasome inhibition represents a clinical challenge, whose biology is poorly understood. Proteasome mutations were implicated as underlying mechanism, while an alternative hypothesis based on low activation status of the unfolded protein response was recently suggested (IRE1/XBP1-low model). We generated bortezomib- and carfilzomib-adapted, highly resistant multiple myeloma cell clones (AMO-BTZ, AMO-CFZ), which we analyzed in a combined quantitative and functional proteomic approach. We demonstrate that proteasome inhibitor-adapted myeloma cells tolerate subtotal proteasome inhibition, irrespective of a proteasome mutation, and uniformly show an 'IRE1/XBP1-low' signature. Adaptation of myeloma cells to proteasome inhibitors involved quantitative changes in >600 protein species with similar patterns in AMO-BTZ and AMO-CFZ cells: proteins involved in metabolic regulation, redox homeostasis, and protein folding and destruction were upregulated, while apoptosis and transcription/translation were downregulated. The quantitatively most upregulated protein in AMO-CFZ cells was the multidrug resistance protein (MDR1) protein ABCB1, and carfilzomib resistance could be overcome by MDR1 inhibition. We propose a model where proteasome inhibitor-adapted myeloma cells tolerate subtotal proteasome inhibition owing to metabolic adaptations that favor the generation of reducing equivalents, such as NADPH, which is supported by oxidative glycolysis. Proteasome inhibitor resistance may thus be targeted by manipulating the energy and redox metabolism.
Gorlaeus Laboratories, Leiden Institute of Chemistry and Netherlands Proteomics Centre, Leiden, The Netherlands.
G P
GP
Soriano
Experimental Oncology and Hematology, Department of Oncology and Hematology, Kantonsspital St Gallen, St Gallen, Switzerland.
L
L
Besse
Gorlaeus Laboratories, Leiden Institute of Chemistry and Netherlands Proteomics Centre, Leiden, The Netherlands.
N
N
Li
Experimental Oncology and Hematology, Department of Oncology and Hematology, Kantonsspital St Gallen, St Gallen, Switzerland.
M
M
Kraus
Experimental Oncology and Hematology, Department of Oncology and Hematology, Kantonsspital St Gallen, St Gallen, Switzerland.
A
A
Besse
Gorlaeus Laboratories, Leiden Institute of Chemistry and Netherlands Proteomics Centre, Leiden, The Netherlands.
N
N
Meeuwenoord
Experimental Oncology and Hematology, Department of Oncology and Hematology, Kantonsspital St Gallen, St Gallen, Switzerland.
J
J
Bader
Department of Parasitology, Leiden University Medical Center, Leiden, The Netherlands.
B
B
Everts
Gorlaeus Laboratories, Leiden Institute of Chemistry and Netherlands Proteomics Centre, Leiden, The Netherlands.
H
H
den Dulk
Gorlaeus Laboratories, Leiden Institute of Chemistry and Netherlands Proteomics Centre, Leiden, The Netherlands.
H S
HS
Overkleeft
Gorlaeus Laboratories, Leiden Institute of Chemistry and Netherlands Proteomics Centre, Leiden, The Netherlands.
B I
BI
Florea
Experimental Oncology and Hematology, Department of Oncology and Hematology, Kantonsspital St Gallen, St Gallen, Switzerland.
C
C
Driessen
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000502:physiology; D000220:Adaptation, Biological; D045744:Cell Line, Tumor; D002999:Clone Cells; D019008:Drug Resistance, Neoplasm; D004734:Energy Metabolism; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D010084:Oxidation-Reduction; D046988:Proteasome Endopeptidase Complex / Q000235:genetics; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D040901:Proteomics
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D061988:Proteasome Inhibitors; D046988:Proteasome Endopeptidase Complex