Inihibition of PI3K by LY294002 promotes apoptosis and dephosphorylates bad in myeloid leukemias

Shourong Zhao, Marina Konopleva, Zhong Xie, Wei Hu, Zeev Estrov, Michèle Milella, Gordon Mills, Michael Andreeff

Research output: Contribution to journalArticle

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Abstract

The PI3K-AKT protein kinase pathway is involved in cell growth, proliferation, cell transformation, and apoptosis. PI3K combined with PDK1 and PDK2 activate AKT. Many molecules are downstream target of this protein kinase, including the pro-apoptotic protein BAD, caspase-9, NFkB, and Forkhead which are all phosphorylated through this pathway. Functional activation of PI3K/AKT may deliver survival signals to cells, particularly to tumor cells and blockade of this pathway may facilitate cell to death. Amplification and increased activity of PI3K have been found in solid tumors. Inhibition of PI3K with LY294002 was found to reduce tumor growth in mice models. We have previously reported that BAD is constitutively phosphorylated in all primary AML, a post- transcriptional modification that converts its function to anti-apoptotic and contributes to drug resistance. In this study, we tested the hypothesis that inhibition of PI3K by LY294002 can dephosphorylate AKT and BAD and promote leukemia cell apoptosis. We investigated the apoptotic effect of LY294002 in cytokine dependent MOVE cells, primary AML samples and normal BM progenitor cells. In MOVE cells, LY294002 reduced AKT kinase activity and induced dephosphorylation of AKT and BAD associated with apoptosis. In primary AML, cell growth in suspension cultures was inhibited and clonogenicity was significantly reduced. LY294002 exerted a synergistic effect with ATRA in inducing apoptosis. Normal hematopoietic progenitor cells were not affected, suggesting selective targeting of leukemia cells.

Original languageEnglish (US)
JournalBlood
Volume96
Issue number11 PART I
StatePublished - Dec 1 2000
Externally publishedYes

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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Myeloid Leukemia
Phosphatidylinositol 3-Kinases
Apoptosis
Tumors
Cell growth
Protein Kinases
Leukemia
Apoptosis Regulatory Proteins
Growth
Caspase 9
Cell proliferation
Cell culture
Neoplasms
Amplification
Suspensions
Phosphotransferases
Hematopoietic Stem Cells
Chemical activation
Cells

ASJC Scopus subject areas

  • Hematology

Cite this

Zhao, S., Konopleva, M., Xie, Z., Hu, W., Estrov, Z., Milella, M., ... Andreeff, M. (2000). Inihibition of PI3K by LY294002 promotes apoptosis and dephosphorylates bad in myeloid leukemias. Blood, 96(11 PART I).

Inihibition of PI3K by LY294002 promotes apoptosis and dephosphorylates bad in myeloid leukemias. / Zhao, Shourong; Konopleva, Marina; Xie, Zhong; Hu, Wei; Estrov, Zeev; Milella, Michèle; Mills, Gordon; Andreeff, Michael.

In: Blood, Vol. 96, No. 11 PART I, 01.12.2000.

Research output: Contribution to journalArticle

Zhao, S, Konopleva, M, Xie, Z, Hu, W, Estrov, Z, Milella, M, Mills, G & Andreeff, M 2000, 'Inihibition of PI3K by LY294002 promotes apoptosis and dephosphorylates bad in myeloid leukemias', Blood, vol. 96, no. 11 PART I.
Zhao S, Konopleva M, Xie Z, Hu W, Estrov Z, Milella M et al. Inihibition of PI3K by LY294002 promotes apoptosis and dephosphorylates bad in myeloid leukemias. Blood. 2000 Dec 1;96(11 PART I).
Zhao, Shourong ; Konopleva, Marina ; Xie, Zhong ; Hu, Wei ; Estrov, Zeev ; Milella, Michèle ; Mills, Gordon ; Andreeff, Michael. / Inihibition of PI3K by LY294002 promotes apoptosis and dephosphorylates bad in myeloid leukemias. In: Blood. 2000 ; Vol. 96, No. 11 PART I.
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