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.
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.
D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides / Q000494:pharmacology; D002087:Butyrates / Q000494:pharmacology; D002867:Chromones / Q000494:pharmacology; D015938:Complement Membrane Attack Complex; D003165:Complement System Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism*; D003574:Cytochrome c Group / Q000187:drug effects; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006023:Glycoproteins / Q000187:drug effects; D018922:HL-60 Cells; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D019169:Jurkat Cells; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D008928:Mitochondria / Q000187:drug effects; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010940:Plant Proteins; D011725:Pyridines / Q000494:pharmacology; D020298:U937 Cells
D001549:Benzamides; D002087:Butyrates; C493956:CDKN1A protein, human; D002867:Chromones; D015938:Complement Membrane Attack Complex; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D003574:Cytochrome c Group; D004791:Enzyme Inhibitors; D006023:Glycoproteins; D056572:Histone Deacetylase Inhibitors; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010940:Plant Proteins; D011725:Pyridines; C047610:SC5b-9 protein complex; C118739:entinostat; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D003165:Complement System Proteins; C101691:MMK4 protein, Medicago sativa; D019950:Mitogen-Activated Protein Kinase 1; D020928:Mitogen-Activated Protein Kinases