title: Deguelin, a selective silencer of the NPM1 mutant, potentiates apoptosis and induces differentiation in AML cells carrying the NPM1 mutation.
abstract: Nucleophosmin (NPM1) is a multifunctional protein that functions as a molecular chaperone, shuttling between the nucleolus and the cytoplasm. In up to one third of patients with acute myeloid leukemia, mutation of NPM1 results in the aberrant cytoplasmic accumulation of mutant protein and is thought to be responsible for leukemogenesis. Deguelin, a rotenoid isolated from several plant species, has been shown to be a strong anti-tumor agent. Human leukemia cell lines were used for in vitro studies. Drug efficacy was evaluated by apoptosis and differentiation assays, and associated molecular events were assessed by Western blot. Gene silencing was performed using small interfering RNA (siRNA). Deguelin exhibited strong cytotoxic activity in the cell line of OCI-AML3 and selectively down-regulated the NPM1 mutant protein, which was accompanied by up-regulation of the activity of caspase-6 and caspase-8 in high concentrations. Deguelin induced differentiation of OCI-AML3 cells at a nontoxic concentration which was associated with a decrease in expression of activated caspase-8, p53, p21, and the 30-kD form of CCAAT/enhancer binding protein α (C/EBPα), whereas no effects were found in OCIM2 cells expressing NPM-wt. Moreover, treatment with siRNA in the NPM mutant cell line OCI-AML3 decreased expression of p53, p21, pro-caspase-8, and the 30-kD form of C/EBPα, and it inhibited proliferation and induced differentiation of the OCI-AML3 cells. In conclusion, deguelin is a potent in vitro inhibitor of the mutant form of NPM1, which provides the molecular basis for its anti-leukemia activities in NPM1 mutant acute myeloid leukemia cells.
authors.affiliation: Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, People's Republic of China.
authors.forename: Sha
authors.initials: S
authors.lastname: Yi
authors.forename: Lu
authors.initials: L
authors.lastname: Wen
authors.forename: Jing
authors.initials: J
authors.lastname: He
authors.forename: Youping
authors.initials: Y
authors.lastname: Wang
authors.forename: Fei
authors.initials: F
authors.lastname: Zhao
authors.forename: Jie
authors.initials: J
authors.lastname: Zhao
authors.forename: Zichu
authors.initials: Z
authors.lastname: Zhao
authors.forename: Guohui
authors.initials: G
authors.lastname: Cui
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000208:Acute Disease; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D015153:Blotting, Western; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000378:metabolism; D053178:Caspase 6 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects* / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D000090243:Nucleophosmin; D034622:RNA Interference; D012402:Rotenone / Q000031:analogs & derivatives* / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D022763:CCAAT-Enhancer-Binding Protein-alpha; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050505:Mutant Proteins; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D016159:Tumor Suppressor Protein p53; D012402:Rotenone; D000090243:Nucleophosmin; D053178:Caspase 6; D053181:Caspase 8; C107676:deguelin