title: Proteasome inhibitors exert cytotoxicity and increase chemosensitivity via transcriptional repression of Notch1 in T-cell acute lymphoblastic leukemia.
abstract: 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.
authors.affiliation: Division of Stem Cell Regulation, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan.
authors.forename: D
authors.initials: D
authors.lastname: Koyama
authors.affiliation: Division of Stem Cell Regulation, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Kikuchi
authors.affiliation: Division of Stem Cell Regulation, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Hiraoka
authors.affiliation: Division of Stem Cell Regulation, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Wada
authors.affiliation: Department of Pediatrics, Dokkyo Medical University, School of Medicine, Tochigi, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Kurosawa
authors.affiliation: Department of Hematology and Tsukuba Advanced Research Alliance, University of Tsukuba, Ibaraki, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Chiba
authors.affiliation: Division of Stem Cell Regulation, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Furukawa
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D050677:Core Binding Factor Alpha 3 Subunit / Q000235:genetics / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D011719:Pyrazines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects*; D014407:Tumor Cells, Cultured
chemical_list: D001897:Boronic Acids; D050677:Core Binding Factor Alpha 3 Subunit; D016328:NF-kappa B; D061988:Proteasome Inhibitors; D011719:Pyrazines; D012333:RNA, Messenger; D051881:Receptor, Notch1; D000069286:Bortezomib