title: Activation of PI3K is indispensable for interleukin 7-mediated viability, proliferation, glucose use, and growth of T cell acute lymphoblastic leukemia cells.
abstract: Interleukin (IL)-7 is essential for normal T cell development. Previously, we have shown that IL-7 increases viability and proliferation of T cell acute lymphoblastic leukemia (T-ALL) cells by up-regulating Bcl-2 and down-regulating the cyclin-dependent kinase inhibitor p27kip1. Here, we examined the signaling pathways via which IL-7 mediates these effects. We investigated mitogen-activated protein kinase (MEK)-extracellular signal-regulated kinase (Erk) and phosphatidylinositol-3-kinase (PI3K)-Akt (protein kinase B) pathways, which have active roles in T cell expansion and have been implicated in tumorigenesis. IL-7 induced activation of the MEK-Erk pathway in T-ALL cells; however, inhibition of the MEK-Erk pathway by the use of the cell-permeable inhibitor PD98059, did not affect IL-7-mediated viability or cell cycle progression of leukemic cells. IL-7 induced PI3K-dependent phosphorylation of Akt and its downstream targets GSK-3, FOXO1, and FOXO3a. PI3K activation was mandatory for IL-7-mediated Bcl-2 up-regulation, p27kip1 down-regulation, Rb hyperphosphorylation, and consequent viability and cell cycle progression of T-ALL cells. PI3K signaling was also required for cell size increase, up-regulation of CD71, expression of the glucose transporter Glut1, uptake of glucose, and maintenance of mitochondrial integrity. Our results implicate PI3K as a major effector of IL-7-induced viability, metabolic activation, growth and proliferation of T-ALL cells, and suggest that PI3K and its downstream effectors may represent molecular targets for therapeutic intervention in T-ALL.
authors.affiliation: Tumor Biology Unit, Institute of Molecular Medicine, University of Lisbon Medical School, 1649-028, Lisbon, Portugal.
authors.forename: Joao T
authors.initials: JT
authors.lastname: Barata
authors.forename: Ana
authors.initials: A
authors.lastname: Silva
authors.forename: Joana G
authors.initials: JG
authors.lastname: Brandao
authors.forename: Lee M
authors.initials: LM
authors.lastname: Nadler
authors.forename: Angelo A
authors.initials: AA
authors.lastname: Cardoso
authors.forename: Vassiliki A
authors.initials: VA
authors.lastname: Boussiotis
mesh_terms: D015703:Antigens, CD / Q000096:biosynthesis; D000944:Antigens, Differentiation, B-Lymphocyte / Q000096:biosynthesis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division; D002470:Cell Survival; D050760:Cyclin-Dependent Kinase Inhibitor p27; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism*; D051272:Glucose Transporter Type 1; D006801:Humans; D015151:Immunoblotting; D016130:Immunophenotyping; D015851:Interleukin-7 / Q000378:metabolism*; D037181:Lectins, C-Type; D008564:Membrane Potentials; D008928:Mitochondria / Q000473:pathology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D011233:Precipitin Tests; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism*; D011990:Receptors, Transferrin; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism*; D013997:Time Factors; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D015854:Up-Regulation; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; D000945:Antigens, Differentiation, T-Lymphocyte; D018797:Cell Cycle Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004791:Enzyme Inhibitors; D005419:Flavonoids; D005947:Glucose; D051272:Glucose Transporter Type 1; D015851:Interleukin-7; D037181:Lectins, C-Type; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D009004:Monosaccharide Transport Proteins; D019869:Phosphatidylinositol 3-Kinases; D011990:Receptors, Transferrin; D025521:Tumor Suppressor Proteins; D000099192:CD69 Antigens; C068126:CD71 antigen; C495677:SLC2A1 protein, human; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one