Interruption of the NF-kappaB pathway by Bay 11-7082 promotes UCN-01-mediated mitochondrial dysfunction and apoptosis in human multiple myeloma cells.
Interactions between pharmacologic NF-kappaB inhibitors (eg, Bay 11-7082, SN-50) and the checkpoint abrogator UCN-01 have been examined in human multiple myeloma (MM) cells. Exposure of U266 cells to Bay 11-7082 (Bay) in combination with UCN-01 resulted in the abrogation of NF-kappaB/DNA binding activity and the synergistic induction of apoptosis. Comparable synergism was observed in other MM cell lines and patient-derived CD138+ cells and between an inhibitory peptide of NF-kappaB (SN50) and UCN-01. Bay/UCN-01-mediated lethality involved mitochondrial dysfunction, caspase cleavage, and poly adenosine diphosphate-ribose polymerase (PARP) degradation. Although Bay modestly blocked UCN-01-induced extracellular signal-regulated kinase (ERK) phosphorylation, coadministration activated c-Jun N-terminal kinase (JNK) and cdc2/cdk1 and down-regulated Mcl-1, XIAP, and Bcl-xL. Transfection with a constitutively activated mitogen-activated protein kinase kinase (MEK1)/green fluorescent protein (GFP) construct failed to block apoptosis induced by Bay/UCN-01 but significantly attenuated MEK inhibitor (U0126)/UCN-01-induced lethality. Inhibiting JNK activation with SP600125 or D-JNKI1 peptide markedly reduced Bay/UCN-01-mediated mitochondrial dysfunction and apoptosis and the down-regulation of Mcl-1, XIAP, and Bcl-xL but not of cdc2/cdk1 activation. Stable transfection of cells with dominant-negative caspase-9 dramatically diminished Bay/UCN-01 lethality without altering JNK or cdc2/cdk1 activation. Neither interleukin-6 (IL-6)- nor fibronectin-mediated adherence conferred resistance to Bay/UCN-01-induced apoptosis. Together, these findings suggest that a strategy combining UCN-01 with disruption of the IkappaB kinase (IKK)/IkappaB/NF-kappaB pathway warrants attention in MM.
Dai
Yun
Y
Department of Medicine, Virginia Commonwealth University, Medical College of Virginia, Richmond 23298, USA.
Pei
Xin-Yan
XY
Rahmani
Mohamed
M
Conrad
Daniel H
DH
Dent
Paul
P
Grant
Steven
S
D015703:Antigens, CD / Q000032:analysis; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects / Q000502:physiology; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D008562:Membrane Glycoproteins / Q000032:analysis; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009101:Multiple Myeloma / Q000473:pathology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009570:Nitriles; D009930:Organic Chemicals / Q000494:pharmacology*; D011509:Proteoglycans / Q000032:analysis; D019311:Staurosporine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D013450:Sulfones; D053668:Syndecan-1; D053667:Syndecans
C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D015703:Antigens, CD; D000970:Antineoplastic Agents; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D009570:Nitriles; D009930:Organic Chemicals; D011509:Proteoglycans; C508241:SDC1 protein, human; D013450:Sulfones; D053668:Syndecan-1; D053667:Syndecans; C054852:7-hydroxystaurosporine; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D019311:Staurosporine