An IkappaBalpha inhibitor causes leukemia cell death through a p38 MAP kinase-dependent, NF-kappaB-independent mechanism

Cancer Res. 2001 Aug 15;61(16):6290-6.

Abstract

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.

MeSH terms

  • Activating Transcription Factor 2
  • Anti-Infective Agents / antagonists & inhibitors
  • Anti-Infective Agents / pharmacology*
  • Apoptosis / drug effects*
  • Apoptosis / physiology
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • DNA-Binding Proteins / antagonists & inhibitors*
  • Dose-Response Relationship, Drug
  • Enzyme Activation
  • Enzyme Inhibitors / pharmacology
  • Humans
  • I-kappa B Proteins*
  • Imidazoles / pharmacology
  • Leukemia, Myeloid / enzymology
  • Leukemia, Myeloid / pathology*
  • MAP Kinase Kinase Kinase 1*
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinases / metabolism
  • Mitogen-Activated Protein Kinases / physiology*
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / physiology*
  • Necrosis
  • Nitriles
  • Phosphorylation
  • Protein Serine-Threonine Kinases / antagonists & inhibitors
  • Pyridines / pharmacology
  • Sulfones
  • Transcription Factors / metabolism
  • Tumor Cells, Cultured / drug effects
  • U937 Cells
  • p38 Mitogen-Activated Protein Kinases

Substances

  • Activating Transcription Factor 2
  • Anti-Infective Agents
  • BAY 11-7085
  • Cyclic AMP Response Element-Binding Protein
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • I-kappa B Proteins
  • Imidazoles
  • NF-kappa B
  • NFKBIA protein, human
  • Nitriles
  • Pyridines
  • Sulfones
  • Transcription Factors
  • NF-KappaB Inhibitor alpha
  • Protein Serine-Threonine Kinases
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinase 1
  • MAP3K1 protein, human
  • SB 203580