Abstract
This study found that phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling was activated in human T-cell lymphotropic virus type I (HTLV-1)-infected leukemia cells. Rapamycin (1-100 nM, 48h), the inhibitor of mTOR and its analog RAD001 (1-100 nM, 48 h)-induced growth inhibition and G0/G1 cell cycle arrest of these cells in association with de-phosphorylation of p70S6K and 4E-BP-1, although IC50 was not achieved. Paradoxically, rapamycin-stimulated phosphorylation of Akt at Ser473. Blockade of Akt signaling by the PI3K inhibitor LY294002 (1-20 microM, 48 h) also resulted in the growth inhibition and G0/G1 cell cycle arrest of HTLV-1-infected cells, with IC50 ranging from 5 to 20muM, and it caused de-phosphorylation of p70S6K and 4E-BP-1. Of note, when rapamycin was combined with LY294002, rapamycin-induced phosphorylation of Akt was blocked, and the ability of rapamycin to induce growth arrest of HTLV-1-infected T-cells and suppress the p-p70S6K and p-4E-BP-1 proteins was potentiated. Moreover, both LY294002 and rapamycin down-regulated the levels of c-Myc and cyclin D1 proteins in these cells, and their combination further decreased levels of these cell cycle-regulating proteins. Taken together, longitudinal inhibition of PI3K/Akt/mTOR signaling represents a promising treatment strategy for individuals with adult T-cell leukemia.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / metabolism
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Cell Cycle / drug effects
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Cell Cycle Proteins
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Chromones / pharmacology*
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Cyclin D
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Cyclins / metabolism
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Enzyme Inhibitors / pharmacology
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Human T-lymphotropic virus 1
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Humans
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Immunosuppressive Agents / pharmacology
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Leukemia-Lymphoma, Adult T-Cell / metabolism
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Leukemia-Lymphoma, Adult T-Cell / pathology*
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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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Phosphoproteins / metabolism
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Phosphorylation / drug effects
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Protein Kinases*
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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-myc / metabolism
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Ribosomal Protein S6 Kinases, 70-kDa / antagonists & inhibitors
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Ribosomal Protein S6 Kinases, 70-kDa / metabolism
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Signal Transduction / drug effects
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Sirolimus / pharmacology*
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T-Lymphocytes / metabolism
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T-Lymphocytes / virology
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TOR Serine-Threonine Kinases
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Tumor Cells, Cultured
Substances
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Adaptor Proteins, Signal Transducing
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Cell Cycle Proteins
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Chromones
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Cyclin D
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Cyclins
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EIF4EBP1 protein, human
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Enzyme Inhibitors
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Immunosuppressive Agents
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MYC protein, human
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Morpholines
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Phosphoinositide-3 Kinase Inhibitors
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Phosphoproteins
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Proto-Oncogene Proteins c-myc
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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Protein Kinases
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MTOR protein, human
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TOR Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Ribosomal Protein S6 Kinases, 70-kDa
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Sirolimus