Inhibition of PI-3 kinase sensitizes human leukemic cells to histone deacetylase inhibitor-mediated apoptosis through p44/42 MAP kinase inactivation and abrogation of p21(CIP1/WAF1) induction rather than AKT inhibition

Oncogene. 2003 Sep 18;22(40):6231-42. doi: 10.1038/sj.onc.1206646.

Abstract

Effects of the PI-3 kinase inhibitor LY294002 (LY) have been examined in relation to responses of human leukemia cells to histone deacetylase inhibitors (HDIs). Coexposure of U937 cells for 24 h to marginally toxic concentrations of LY294002 (e.g., 30 microM) and sodium butyrate (SB; 1 mM) resulted in a marked increase in mitochondrial damage (e.g., cytochrome c and Smac/DIABLO release, loss of DeltaPsi(m)), caspase activation, and apoptosis. Similar results were observed in Jurkat, HL-60, and K562 leukemic cells and with other HDIs (e.g., SAHA, MS-275). Exposure of cells to SB/LY was associated with Bcl-2 and Bid cleavage, XIAP and Mcl-1 downregulation, and diminished CD11b expression. While LY blocked SB-mediated Akt activation, enforced expression of a constitutively active (myristolated) Akt failed to attenuate SB/LY-mediated lethality. Unexpectedly, treatment of cells with SB+/-LY resulted in a marked reduction in phosphorylation (activation) of p44/42 mitogen-activated protein (MAP) kinase. Moreover, enforced expression of a constitutively active MEK1 construct partially but significantly attenuated SB/LY-induced apoptosis. Lastly, cotreatment with LY blocked SB-mediated induction of p21(CIP1/WAF1); moreover, enforced expression of p21(CIP1/WAF1) significantly reduced SB/LY-mediated apoptosis. Together, these findings indicate that LY promotes SB-mediated apoptosis through an AKT-independent process that involves MEK/MAP kinase inactivation and interference with p21(CIP1/WAF1) induction.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Apoptosis / drug effects*
  • Benzamides / pharmacology
  • Butyrates / pharmacology
  • Chromones / pharmacology
  • Complement Membrane Attack Complex
  • Complement System Proteins
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins / metabolism*
  • Cytochrome c Group / drug effects
  • Drug Synergism
  • Enzyme Inhibitors / pharmacology
  • Glycoproteins / drug effects
  • HL-60 Cells
  • Histone Deacetylase Inhibitors*
  • Humans
  • Jurkat Cells
  • K562 Cells
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / enzymology
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
  • Mitochondria / drug effects
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Mitogen-Activated Protein Kinases / metabolism*
  • Morpholines / pharmacology
  • Phosphoinositide-3 Kinase Inhibitors*
  • Plant Proteins
  • Pyridines / pharmacology
  • U937 Cells

Substances

  • Benzamides
  • Butyrates
  • CDKN1A protein, human
  • Chromones
  • Complement Membrane Attack Complex
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • Cytochrome c Group
  • Enzyme Inhibitors
  • Glycoproteins
  • Histone Deacetylase Inhibitors
  • Morpholines
  • Phosphoinositide-3 Kinase Inhibitors
  • Plant Proteins
  • Pyridines
  • SC5b-9 protein complex
  • entinostat
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Complement System Proteins
  • MMK4 protein, Medicago sativa
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinases