Targeting of active mTOR inhibits primary leukemia T cells and synergizes with cytotoxic drugs and signaling inhibitors
| Autor: | Elke Raderschall, João T. Barata, Stephen E. Sallan, Lee M. Nadler, Ana Batista, Angelo A. Cardoso, Nadia Carlesso |
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| Rok vydání: | 2010 |
| Předmět: |
Cancer Research
Cell Survival medicine.medical_treatment Morpholines Immunoblotting Pharmacology Biology Precursor T-Cell Lymphoblastic Leukemia-Lymphoma Dexamethasone Cell Line Tumor Genetics medicine Humans Enzyme Inhibitors Phosphorylation Molecular Biology Protein kinase B PI3K/AKT/mTOR pathway Cell Proliferation Phosphoinositide-3 Kinase Inhibitors Sirolimus Tumor microenvironment Antibiotics Antineoplastic Janus kinase 3 TOR Serine-Threonine Kinases RPTOR Cell Cycle Janus Kinase 3 Drug Synergism Cell Biology Hematology medicine.disease Immunohistochemistry Leukemia Cytokine Microscopy Fluorescence Chromones Doxorubicin Quinazolines Signal transduction Phosphatidylinositol 3-Kinase Eukaryotic Initiation Factor-4G Proto-Oncogene Proteins c-akt Signal Transduction |
| Zdroj: | Experimental hematology. 39(4) |
| ISSN: | 1873-2399 |
| Popis: | Objective Rationally designed therapies aim at the specific disruption of critical signaling pathways activated by malignant transformation or signals from the tumor microenvironment. Because mammalian target of rapamycin (mTOR) is an important signal integrator and a key translational regulator, we evaluated its potential involvement in T-cell acute lymphoblastic leukemia (T-ALL) and whether mTOR blockade synergizes with chemotherapeutic agents or other signaling antagonists to inhibit primary leukemia T cells. Materials and Methods mTOR signaling status was assessed using biochemical, immunostaining, and molecular regulation studies and functional assays performed to assess the impact of mTOR blockade on T-ALL proliferation, survival, and cell cycle. Results We observed that mTOR signaling is highly activated in all T-ALL patients tested, with phosphorylation of its downstream substrates eIF4G and S6 ribosomal protein. mTOR activation was detected in vivo and was further increased in vitro by stimulation with interleukin-7, a potentially leukemogenic cytokine normally produced by the bone marrow microenvironment. In T-ALL cells, mTOR blockade was associated with accumulation of the cyclin-dependent kinase inhibitor p27 kip1 , which preferentially adopted a nuclear localization. Functional studies using rapamycin or CCI-779 showed a dominant inhibitory effect of mTOR blockade on interleukin-7−induced proliferation, survival, and cell-cycle progression of T-ALL cells. Furthermore, mTOR blockade markedly potentiated the antileukemia effects of dexamethasone and doxorubicin, and showed highly synergistic interactions in combination with specific inhibitors of phosphatidylinositol 3-kinase/Akt and Janus kinase 3 signaling. Conclusions This study shows activation of mTOR signaling in primary T-ALL cells evolving in the leukemic bone marrow, and supports the inclusion of mTOR antagonists in current therapeutic regimens for this cancer. |
| Databáze: | OpenAIRE |
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