Involvement of Akt kinase in the action of STI571 on chronic myelogenous leukemia cells

Blood Cells Mol Dis. Jul-Aug 2003;31(1):11-7. doi: 10.1016/s1079-9796(03)00070-6.

Abstract

To elucidate the role of mitogen-activated protein kinases (MAPKs) and Akt kinase in leukemogenesis caused by the breakpoint cluster region (BCR)-Abelson (ABL) tyrosine kinase oncoprotein, we examined the activities of MAPKs and Akt kinase and their roles in the action of STI571, a specific inhibitor of BCR-ABL tyrosine kinase, in chronic myelogenous leukemia (CML) cells. We found that extracellular signal-regulated kinase (ERK) 1/2 and Akt kinase are constitutively active in the chronic phase of CML, blast crisis of CML, and the CML-derived K562 cell line. Both interferon-alpha and STI571 suppressed ERK1/2 activity in K562 cells. In contrast, Akt kinase activity was inhibited only by STI571. K562 cell proliferation was markedly suppressed by LY294002, a specific inhibitor of PI3K/Akt kinase, and STI571 but not by PD98059, a specific inhibitor of MEK1/2. In addition, caspase-3 was activated by treatment of cells with STI571 and LY294002 but not with PD98059. These data indicate that Akt kinase may play a role in the proliferation of CML leukemia cells and the action of STI571. Primary leukemia cells from patients with CML blast crisis did not show inhibition of ERK1/2 or Akt kinase activity and were resistant to caspase-3-associated apoptosis after treatment with STI571. These findings suggest that STI571 does not effectively block signaling molecules downstream of the BCR-ABL tyrosine kinase in some cases of CML blast crisis.

MeSH terms

  • Adult
  • Aged
  • Apoptosis / drug effects
  • Benzamides
  • Blast Crisis / pathology
  • Cell Division / drug effects
  • Cell Line, Tumor
  • Female
  • Humans
  • Imatinib Mesylate
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / enzymology
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / etiology*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
  • Leukemia, Myeloid, Chronic-Phase / pathology
  • Male
  • Middle Aged
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinases / physiology
  • Piperazines / pharmacology*
  • Protein-Serine-Threonine Kinases*
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Proto-Oncogene Proteins / physiology*
  • Proto-Oncogene Proteins c-akt
  • Pyrimidines / pharmacology*
  • Tumor Cells, Cultured

Substances

  • Benzamides
  • Piperazines
  • Proto-Oncogene Proteins
  • Pyrimidines
  • Imatinib Mesylate
  • Protein-Tyrosine Kinases
  • AKT1 protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases