Longitudinal inhibition of PI3K/Akt/mTOR signaling by LY294002 and rapamycin induces growth arrest of adult T-cell leukemia cells
| Autor: | H. Phillip Koeffler, Chie Nishioka, Yang Yang, Hirokuni Taguchi, Takayuki Ikezoe, Yoshihiro Adachi, Yoshio Kuwayama, Kentaro Bandobashi, Tamotsu Takeuchi |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2007 |
| Předmět: |
Cancer Research
Morpholines T-Lymphocytes T-cell leukemia Cell Cycle Proteins Biology PI3K Proto-Oncogene Proteins c-myc Phosphatidylinositol 3-Kinases chemistry.chemical_compound Cyclin D Cyclins Tumor Cells Cultured Humans Leukemia-Lymphoma Adult T-Cell LY294002 Enzyme Inhibitors Phosphorylation p70S6K Protein kinase B PI3K/AKT/mTOR pathway Adaptor Proteins Signal Transducing Phosphoinositide-3 Kinase Inhibitors Sirolimus Human T-lymphotropic virus 1 TOR Serine-Threonine Kinases Akt Cell Cycle RPTOR Ribosomal Protein S6 Kinases 70-kDa 4E-BP-1 Hematology Phosphoproteins Cell biology Oncology chemistry Chromones ATL mTOR Growth inhibition Protein Kinases Proto-Oncogene Proteins c-akt Immunosuppressive Agents Signal Transduction |
| Zdroj: | Leukemia research. 31(5):673-682 |
| ISSN: | 0145-2126 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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