An IkappaBalpha inhibitor causes leukemia cell death through a p38 MAP kinase-dependent, NF-kappaB-independent mechanism.
Treatment of U937 cells with an IkappaBalpha phosphorylation inhibitor, Bay 11-7085, induced a rapid phosphorylation of p38 mitogen-activated protein (MAP) kinase, significant apoptosis, extensive necrosis, and a weak phosphorylation of MAP kinase kinase. Bay 11-7085 had no effect on the basal levels of phosphorylated IkappaBalpha but completely inhibited phorbol 12-myristate 13-acetate-induced phosphorylation of IkappaBalpha. Although Bay 11-7085 prevented phorbol 12-myristate 13-acetate-induced NF-kappaB nuclear translocation, SN50, a specific inhibitor of nuclear translocation and function of NF-kappaB, did not induce any significant nuclear/DNA fragmentation, caspase 3 activation, or cell death. The p38 MAP kinase-specific inhibitor, SB203580, completely inhibited the phosphorylation of p38 MAP kinase and significantly decreased Bay 11-7085-induced apoptosis. In contrast, the MAP kinase kinase-specific inhibitor PD98059 had no effect on Bay 11-7085-induced apoptosis. Caspase-specific inhibitor, z-Val-Ala-Asp-fluoromethyl ketone prevented Bay 11-7085-induced activation of caspase 3 but was not able to block Bay 11-7085-induced phosphorylation of p38 MAP kinase. These data suggest that Bay 11-7085 induces apoptosis through a p38 MAP kinase-dependent, NF-kappaB-independent mechanism.
Hu
X
X
Interdisciplinary Oncology Program, University of South Florida, and the H. Lee Moffitt Cancer Center, Tampa, Florida 33612, USA. hu@moffitt@usf.edu
Janssen
W E
WE
Moscinski
L C
LC
Bryington
M
M
Dangsupa
A
A
Rezai-Zadeh
N
N
Babbin
B A
BA
Zuckerman
K S
KS
D051698:Activating Transcription Factor 2; D000890:Anti-Infective Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D020672:I-kappa B Proteins; D007093:Imidazoles / Q000494:pharmacology; D007951:Leukemia, Myeloid / Q000201:enzymology / Q000473:pathology*; D048728:MAP Kinase Kinase Kinase 1; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000502:physiology*; D009336:Necrosis; D009570:Nitriles; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000494:pharmacology; D013450:Sulfones; D014157:Transcription Factors / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects; D020298:U937 Cells; D048051:p38 Mitogen-Activated Protein Kinases
D051698:Activating Transcription Factor 2; D000890:Anti-Infective Agents; C416282:BAY 11-7085; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D020672:I-kappa B Proteins; D007093:Imidazoles; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D009570:Nitriles; D011725:Pyridines; D013450:Sulfones; D014157:Transcription Factors; D000072000:NF-KappaB Inhibitor alpha; D017346:Protein Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human; C093642:SB 203580