An integrated approach to elucidate signaling pathways of dioscin-induced apoptosis, energy metabolism and differentiation in acute myeloid leukemia
Journal
Naunyn-Schmiedeberg's Archives of Pharmacology
Journal Volume
391
Journal Issue
6
Pages
587
Date Issued
2018-06-01
Author(s)
Abstract
Although the therapeutics have improved the rates of remission and cure of acute myelogenous leukemia (AML) in recent decades, there is still an unmet medical need for AML therapies because disease relapses are a major obstacle in patients who become refractory to salvage therapy. The development of therapeutic agents promoting both cytotoxicity and cell differentiation may provide opportunities to improve the clinical outcome. Dioscin-induced apoptosis in leukemic cells was identified through death receptor-mediated extrinsic apoptosis pathway. The formation of Bak and tBid, and loss of mitochondrial membrane potential were induced by dioscin suggesting the activation of intrinsic apoptotsis pathway. A functional analysis of transcription factors using transcription factor-DNA interaction array and IPA analysis demonstrated that dioscin induced a profound increase of protein expression of CCAAT/enhancer-binding protein α (C/EBPα), a critical factor for myeloid differentiation. Two-dimensional gel electrophoresis assay confirmed the increase of C/EBPα expression. Dioscin-induced differentiation was substantiated by an increase of CD11b protein expression and the induction of differentiation toward myelomonocytic/granulocytic lineages using hematoxylin and eosin staining. Moreover, both glycolysis and gluconeogenesis pathways after two-dimensional gel electrophoresis assay and IPA network enrichment analysis were proposed to dioscin action. In conclusion, the data suggest that dioscin exerts its antileukemic effect through the upregulation of both death ligands and death receptors and a crosstalk activation of mitochondrial apoptosis pathway with the collaboration of tBid and Bak formation. In addition, proteomics approach reveals an altered metabolic signature of dioscin-treated cells and the induction of differentiation of promyelocytes to granulocytes and monocytes in which the C/EBPα plays a key role. ? 2018, Springer-Verlag GmbH Germany, part of Springer Nature.
Subjects
C/EBPα; Death receptor signaling pathway; Differentiation; Dioscin; Ingenuity pathway analysis; Leukemia
SDGs
Other Subjects
antileukemic agent; CCAAT enhancer binding protein alpha; CD11b antigen; dioscin; natural product; protein Bak; transcription factor; tumor necrosis factor receptor; unclassified drug; antineoplastic agent; dioscin; diosgenin; acute myeloid leukemia; apoptosis; Article; cell differentiation; cell structure; controlled study; energy metabolism; gluconeogenesis; glycolysis; granulocyte; human; human cell; mitochondrial membrane potential; monocyte; protein expression; proteomics; signal transduction; two dimensional gel electrophoresis; upregulation; acute myeloid leukemia; analogs and derivatives; apoptosis; cell differentiation; drug effect; energy metabolism; metabolism; signal transduction; tumor cell line; Antineoplastic Agents; Apoptosis; Cell Differentiation; Cell Line, Tumor; Diosgenin; Energy Metabolism; Humans; Leukemia, Myeloid, Acute; Proteomics; Signal Transduction
Type
journal article