title: PI3K/AKT inhibition induces caspase-dependent apoptosis in HTLV-1-transformed cells.
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.
authors.affiliation: Virus Tumor Biology Section, Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Soo-Jin
authors.initials: SJ
authors.lastname: Jeong
authors.forename: Arindam
authors.initials: A
authors.lastname: Dasgupta
authors.forename: Kyung-Jin
authors.initials: KJ
authors.lastname: Jung
authors.forename: Jee-Hyun
authors.initials: JH
authors.lastname: Um
authors.forename: Aileen
authors.initials: A
authors.lastname: Burke
authors.forename: Hyeon Ung
authors.initials: HU
authors.lastname: Park
authors.forename: John N
authors.initials: JN
authors.lastname: Brady
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D053453:Caspase 9 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D002461:Cell Line, Transformed; D002867:Chromones / Q000494:pharmacology; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000494:pharmacology; D045304:Cytochromes c / Q000378:metabolism; D015368:Human T-lymphotropic virus 1 / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology*; D006801:Humans; D008954:Models, Biological; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction; D013876:Thiophenes / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051025:bcl-Associated Death Protein / Q000378:metabolism
chemical_list: D053453:Caspase 9; D002867:Chromones; D050760:Cyclin-Dependent Kinase Inhibitor p27; D045304:Cytochromes c; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; D013876:Thiophenes; D016159:Tumor Suppressor Protein p53; D051025:bcl-Associated Death Protein; C494819:BAD protein, human; C477523:SC 514; C495901:TP53 protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C506433:CASP9 protein, human