Inhibition of phosphatidylinositol 3-kinase dephosphorylates BAD and promotes apoptosis in myeloid leukemias

S. Zhao, M. Konopleva, M. Cabreira-Hansen, Z. Xie, W. Hu, M. Milella, Z. Estrov, G. B. Mills, M. Andreeff

Research output: Contribution to journalArticle

130 Citations (Scopus)

Abstract

The phosphatidylinositol 3-kinase (PI3K)/AKT protein kinase pathways is involved in cell growth, proliferation, and apoptosis. The functional activation of PI3K/AKT provides survival signals and blockade of this pathway may facilitate cell death. Down-stream targets of PI3K-AKT include the proapoptotic protein BAD, caspase-9, NFκB, and Forkhead. We have previously reported that BAD is constitutively phosphorylated in primary acute myeloid leukemia (AML) cells, a post-transcriptional modification, which inactivates its proapoptotic function. In this study, we tested the hypothesis that the inhibition of PI3K by LY294002 results in the dephosphorylation of AKT and BAD, and thus promote leukemia cell apoptosis. We investigated the effects of LY294002 in megakaryocytic leukemia-derived MO7E cells, primary AML and normal bone marrow progenitor cells. In MO7E cells. LY294002 reduced AKT kinase activity, induced dephosphorylation of AKT and BAD, and increased apoptosis. Concomitant inhibition of mitogen-activated protein kinase signaling or combination with all-trans retinoic acid further enhanced apoptosis of leukemic cells. In primary AML samples, clonogenic cell growth was significantly reduced. Normal hematopoietic progenitors were less affected, suggesting preferential targeting of leukemia cells. In conclusion, the data suggest that the inhibition of the PI3K/AKT signaling pathway restores apoptosis in AML and may be explored as a novel target for molecular therapeutic in AML.

Original languageEnglish
Pages (from-to)267-275
Number of pages9
JournalLeukemia
Volume18
Issue number2
DOIs
Publication statusPublished - Feb 2004

Fingerprint

Phosphatidylinositol 3-Kinase
Myeloid Leukemia
Acute Myeloid Leukemia
Apoptosis
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Leukemia
Leukemia, Megakaryoblastic, Acute
Caspase 9
Myeloid Cells
Growth
Tretinoin
Mitogen-Activated Protein Kinases
Bone Marrow Cells
Protein Kinases
Signal Transduction
Cell Death
Phosphotransferases
Stem Cells
Cell Proliferation

Keywords

  • AML and apoptosis
  • BAD phosphorylation
  • LY294002
  • MO7E
  • PI3K-AKT

ASJC Scopus subject areas

  • Hematology
  • Cancer Research

Cite this

Inhibition of phosphatidylinositol 3-kinase dephosphorylates BAD and promotes apoptosis in myeloid leukemias. / Zhao, S.; Konopleva, M.; Cabreira-Hansen, M.; Xie, Z.; Hu, W.; Milella, M.; Estrov, Z.; Mills, G. B.; Andreeff, M.

In: Leukemia, Vol. 18, No. 2, 02.2004, p. 267-275.

Research output: Contribution to journalArticle

Zhao, S, Konopleva, M, Cabreira-Hansen, M, Xie, Z, Hu, W, Milella, M, Estrov, Z, Mills, GB & Andreeff, M 2004, 'Inhibition of phosphatidylinositol 3-kinase dephosphorylates BAD and promotes apoptosis in myeloid leukemias', Leukemia, vol. 18, no. 2, pp. 267-275. https://doi.org/10.1038/sj.leu.2403220
Zhao, S. ; Konopleva, M. ; Cabreira-Hansen, M. ; Xie, Z. ; Hu, W. ; Milella, M. ; Estrov, Z. ; Mills, G. B. ; Andreeff, M. / Inhibition of phosphatidylinositol 3-kinase dephosphorylates BAD and promotes apoptosis in myeloid leukemias. In: Leukemia. 2004 ; Vol. 18, No. 2. pp. 267-275.
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