Denbinobin induces human glioblastoma multiforme cell apoptosis through the IKKα-Akt-FKHR signaling cascade
Journal
European Journal of Pharmacology
Journal Volume
698
Journal Issue
1-3
Pages
103-109
Date Issued
2013
Author(s)
CHE-MING TENG
Abstract
Denbinobin, a phenanthraquinone derivative, was shown to exert antitumor activities in several types of cancer cell lines. However, the precise mechanism underlying denbinobin-induced cell death remains unclear. In this study, we investigated the apoptotic signaling cascade elicited by denbinobin in human glioblastoma multiforme (GBM) cells. Denbinobin concentration-dependently caused a decrease in the cell viability of GBM cells. A flow cytometric analysis of propidium iodide (PI)-stained cells demonstrated that denbinobin induced GBM cell apoptosis. Denbinobin evoked caspase-3 activation and degradation of poly (ADP-ribose) polymerase (PARP) and N-benzyloxycarbonyl-Val-Ala-Asp- fluoromethylketone (zVAD-fmk), a broad-spectrum caspase inhibitor that prevented denbinobin-induced cell death. In addition, denbinobin-induced cell death was diminished by the transfection of wild-type (WT) Akt or IκB kinase (IKK) into GBM cells. Denbinobin reduced IKK phosphorylation in a time-dependent manner, and denbinobin-dephosphorylated IKK was accompanied by a decrease in Akt phosphorylation. The phosphorylation status of forkhead in rhabdomyosarcoma (FKHR), a downstream signal molecule of Akt, was also diminished by the presence of denbinobin. Furthermore, transfection of GBM cells with WT IKKα markedly suppressed the decreases in Akt and FKHR phosphorylation caused by denbinobin. In contrast, transfection with WT IKKβ only slightly affected denbinobin's action against IKK, Akt, and FKHR. These results suggest that IKKα inactivation, followed by Akt and FKHR dephosphorylation and caspase-3 activation, contributes to denbinobin-induced GBM cell apoptosis. ? 2012 Elsevier B.V. All rights reserved.
Subjects
Akt; Denbinobin; FKHR; Glioblastoma multiforme; IKK
SDGs
Other Subjects
antineoplastic agent; caspase 3; denbinobin; I kappa B kinase alpha; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase; protein kinase B; transcription factor FKHR; unclassified drug; antineoplastic activity; apoptosis; article; cancer cell; cell viability; concentration response; controlled study; drug mechanism; enzyme activation; enzyme degradation; enzyme inactivation; enzyme phosphorylation; flow cytometry; human; human cell; priority journal; protein cleavage; protein phosphorylation; signal transduction; Anthraquinones; Antineoplastic Agents; Apoptosis; Caspase 3; Cell Line, Tumor; Enzyme Activation; Forkhead Transcription Factors; Glioblastoma; Humans; I-kappa B Kinase; Phenanthrenes; Phosphorylation; Poly(ADP-ribose) Polymerases; Proteolysis; Proto-Oncogene Proteins c-akt; Signal Transduction
Type
journal article