Abstract
The phosphatidylinositol-3-kinase (PI3K) and AKT (protein kinase B) signaling pathways play an important role in regulating cell cycle progression and cell survival. In previous studies, we demonstrated that AKT is activated in HTLV-1-transformed cells and that Tax activation of AKT is linked to p53 inhibition and cell survival. In the present study, we extend these observations to identify regulatory pathways affected by AKT in HTLV-1-transformed cells. We demonstrate that inhibition of AKT reduces the level of phosphorylated Bad, an important member of the pro-apoptotic family of proteins. Consistent with the decrease of phosphorylated Bad, cytochrome c is released from the mitochondria and caspase-9 is activated. Pretreatment of the cells with caspase-9 specific inhibitor z-LEHD-FMK or pan caspase inhibitor Ac-DEVD-CHO prevented LY294002-induced apoptosis. Of interest, p53 siRNA prevents LY294002-induced apoptosis in HTLV-1-transformed cells, suggesting that p53 reactivation is linked to apoptosis. In conclusion, the AKT pathway is involved in targeting multiple proteins which regulate caspase- and p53-dependent apoptosis in HTLV-1-transformed cells. Since AKT inhibitors simultaneously inhibit NF-kappaB and activate p53, these drugs should be promising candidates for HTLV-1-associated cancer therapy.
Publication types
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Research Support, N.I.H., Intramural
MeSH terms
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Apoptosis / drug effects
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Apoptosis / physiology*
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Caspase 9 / metabolism
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Cell Cycle / drug effects
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Cell Cycle / physiology
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Cell Line, Transformed
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Chromones / pharmacology
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Cyclin-Dependent Kinase Inhibitor p27 / pharmacology
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Cytochromes c / metabolism
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Human T-lymphotropic virus 1 / genetics
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Human T-lymphotropic virus 1 / pathogenicity*
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Human T-lymphotropic virus 1 / physiology*
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Humans
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Models, Biological
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Morpholines / pharmacology
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors*
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Phosphorylation
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Protein Kinase Inhibitors / pharmacology
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
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Proto-Oncogene Proteins c-akt / metabolism
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Signal Transduction
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Thiophenes / pharmacology
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Tumor Suppressor Protein p53 / metabolism
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bcl-Associated Death Protein / metabolism
Substances
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BAD protein, human
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Chromones
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Morpholines
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Phosphoinositide-3 Kinase Inhibitors
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins c-bcl-2
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SC 514
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TP53 protein, human
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Thiophenes
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Tumor Suppressor Protein p53
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bcl-Associated Death Protein
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Cyclin-Dependent Kinase Inhibitor p27
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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Cytochromes c
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Proto-Oncogene Proteins c-akt
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CASP9 protein, human
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Caspase 9