Constitutive NF-kappaB DNA-binding activity in AML is frequently mediated by a Ras/PI3-K/PKB-dependent pathway

Leukemia. 2004 Jan;18(1):103-12. doi: 10.1038/sj.leu.2403145.

Abstract

In the present study, we aimed to elucidate the mechanism responsible for constitutive NF-kappaB DNA-binding activity in AML cells. Intervening in aberrant signaling pathway provides a rational approach for in vivo targeting of AML cells. Constitutive NF-kappaB DNA-binding activity was observed in 16 of 22 (73%) investigated AML cases and was, in general, associated with resistance to spontaneous apoptosis. Indeed, inhibition of NF-kappaB activity by the NF-kappaB inhibitor SN-50 peptide resulted in enhanced chemotherapy-induced apoptosis. In the majority of cases, constitutive NF-kappaB activity was mediated by a Ras/PI3 kinase (PI3-K)/protein kinase B (PKB)-mediated pathway. The PI3-K inhibitor Ly294002 and the Ras inhibitor L-744832 both inhibited PKB phosphorylation and NF-kappaB DNA-binding activity. The constitutive activation of Ras GTP-ase was caused by mutations in the gene encoding for N-Ras in 29% of the cases. The constitutive NF-kappaB activity could so far not be ascribed to the autocrine production of growth factors or to mutations in the Flt3 receptor, since anti-GM-CSF, -IL-1, -IL6, -TNFalpha or the tyrosine kinase inhibitor AG1296 did not affect the NF-kappaB DNA-binding activity. The present study demonstrates that Ras activation is an important pathway for triggering the NF-kappaB pathway in AML cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Apoptosis
  • Chromones / pharmacology
  • DNA, Neoplasm / metabolism
  • Enzyme Activation
  • Enzyme Inhibitors / pharmacology
  • Genes, Reporter
  • Growth Substances / metabolism
  • Humans
  • Leukemia, Myeloid / classification
  • Leukemia, Myeloid / genetics
  • Leukemia, Myeloid / metabolism*
  • Methionine / analogs & derivatives*
  • Methionine / pharmacology
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases / metabolism
  • Morpholines / pharmacology
  • Mutation
  • NF-kappa B / metabolism*
  • Oncogene Protein p21(ras) / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphorylation
  • Protein-Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Signal Transduction*
  • Transcription, Genetic
  • Transfection
  • Tumor Cells, Cultured
  • fms-Like Tyrosine Kinase 3

Substances

  • Chromones
  • DNA, Neoplasm
  • Enzyme Inhibitors
  • Growth Substances
  • L 744832
  • Morpholines
  • NF-kappa B
  • Phosphoinositide-3 Kinase Inhibitors
  • Proto-Oncogene Proteins
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Methionine
  • FLT3 protein, human
  • Receptor Protein-Tyrosine Kinases
  • fms-Like Tyrosine Kinase 3
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • Oncogene Protein p21(ras)