Proteasome inhibitors exert cytotoxicity and increase chemosensitivity via transcriptional repression of Notch1 in T-cell acute lymphoblastic leukemia
| Autor: | Nobuya Hiraoka, Yusuke Furukawa, Hidemitsu Kurosawa, Shigeru Chiba, Tomoaki Wada, Jiro Kikuchi, Daisuke Koyama |
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| Rok vydání: | 2013 |
| Předmět: |
Chromatin Immunoprecipitation
Cancer Research Transcription Genetic T cell Blotting Western Notch signaling pathway Apoptosis Mice SCID Biology Precursor T-Cell Lymphoblastic Leukemia-Lymphoma Real-Time Polymerase Chain Reaction Sp1 Bortezomib Mice Transactivation Mice Inbred NOD hemic and lymphatic diseases Tumor Cells Cultured medicine Animals Humans Cytotoxic T cell RNA Messenger Receptor Notch1 HES1 Cell Proliferation Notch1 proteasome inhibitor Reverse Transcriptase Polymerase Chain Reaction NF-kappa B Hematology chemosensitization Boronic Acids Molecular biology Core Binding Factor Alpha 3 Subunit medicine.anatomical_structure Oncology Proteasome Drug Resistance Neoplasm Pyrazines Proteasome inhibitor Cancer research Original Article Proteasome Inhibitors T-cell acute lymphoblastic leukemia Signal Transduction medicine.drug |
| Zdroj: | Leukemia |
| ISSN: | 1476-5551 0887-6924 |
| Popis: | The Notch signaling pathway has been recognized as a key factor for the pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL), because of the high incidence of activating mutations of Notch1. Notch inhibition could serve as a new treatment strategy for T-ALL; however, the attempts to perturb Notch signaling pathways have been unsuccessful so far. In this study, we found that proteasome inhibitors exert cytotoxic effects on T-ALL cells with constitutive activation of Notch1 to a similar extent as myeloma cells. The proteasome inhibitor bortezomib repressed the transcription of Notch1 and downstream effectors including Hes1, GATA3, RUNX3 and nuclear factor-κB (NF-κB) (p65 and p50), coincided with downregulation of the major transactivator Sp1 and its dissociation from Notch1 promoter. Overexpression of the Notch1 intracellular domain (NICD) significantly ameliorated bortezomib-induced cytotoxicity against T-ALL cells. Drug combination studies revealed that bortezomib showed synergistic or additive effects with key drugs for the treatment of T-ALL such as dexamethasone (DEX), doxorubicin and cyclophosphamide, which were readily abolished by NICD overexpression. The synergy of bortezomib and DEX was confirmed in vivo using a murine xenograft model. Our findings provide a molecular basis and rationale for the inclusion of proteasome inhibitors in treatment strategies for T-ALL. |
| Databáze: | OpenAIRE |
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