PI3-kinase/Akt is constitutively active in primary acute myeloid leukaemia cells and regulates survival and chemoresistance via NF-kappaB, Mapkinase and p53 pathways

Leukemia. 2005 Apr;19(4):586-94. doi: 10.1038/sj.leu.2403653.

Abstract

The phosphoinositide 3-kinase (PI3-kinase) signalling pathway plays a key role in the regulation of cell survival and proliferation. We show that the PI3-kinase/Akt pathway is constitutively active in primary acute myeloid leukaemia (AML) cells and that blockade by the selective inhibitor LY294002 reduces survival of the total blast population (mean 52%). The ERK/MAPK module is also constitutively active and treatment with the MAPKK inhibitor U0126 reduces cell survival by 22%. In 10 of 18 samples, PI3-kinase contributes to MAPK activation as incubation with LY294002 leads to a marked reduction in its phosphorylation. PI3-kinase inhibition reduces survival of the CD34+38- AML progenitor subset by 44%, whereas MAPKK inhibition has little effect. Reporter assays in primary AML cells show that blocking PI3-kinase leads to a marked reduction of constitutive NF-kappaB activity and promotes p53-mediated transcription. This is associated with a synergistic interaction between LY294002 and Ara-C. An inducible activated form of Akt protects normal myeloid cells from Ara-C and etoposide-mediated apoptosis. These results show that blocking PI3-kinase has direct antileukaemic effects and potentiates the response to conventional cytotoxics via a number of targets including NF-kappaB, p53 and MAPK. Inhibitors of PI3-kinase and Akt may be useful in the treatment of AML.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADP-ribosyl Cyclase / metabolism
  • ADP-ribosyl Cyclase 1
  • Acute Disease
  • Animals
  • Antigens, CD / metabolism
  • Antigens, CD34 / metabolism
  • Antimetabolites, Antineoplastic / pharmacology
  • Cell Survival / physiology
  • Chromones / pharmacology
  • Cytarabine / pharmacology
  • Drug Resistance, Neoplasm
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Leukemia, Myeloid / drug therapy
  • Leukemia, Myeloid / metabolism*
  • Leukemia, Myeloid / pathology
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / physiology*
  • Membrane Glycoproteins
  • Morpholines / pharmacology
  • NF-kappa B / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • Antigens, CD
  • Antigens, CD34
  • Antimetabolites, Antineoplastic
  • Chromones
  • Enzyme Inhibitors
  • Membrane Glycoproteins
  • Morpholines
  • NF-kappa B
  • Phosphoinositide-3 Kinase Inhibitors
  • Proto-Oncogene Proteins
  • Tumor Suppressor Protein p53
  • Cytarabine
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • AKT1 protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • ADP-ribosyl Cyclase
  • CD38 protein, human
  • ADP-ribosyl Cyclase 1