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.

Original languageEnglish
Pages (from-to)103-109
Number of pages7
JournalEuropean Journal of Pharmacology
Volume698
Issue number1-3
DOIs
Publication statusPublished - Jan 5 2013

Fingerprint

Rhabdomyosarcoma
Glioblastoma
Apoptosis
Phosphorylation
Transfection
Cell Death
denbinobin
Caspase 3
Caspase Inhibitors
Poly(ADP-ribose) Polymerases
Propidium
Cell Survival

Keywords

  • Akt
  • Denbinobin
  • FKHR
  • Glioblastoma multiforme
  • IKK

ASJC Scopus subject areas

  • Pharmacology

Cite this

Denbinobin induces human glioblastoma multiforme cell apoptosis through the IKKα-Akt-FKHR signaling cascade. / Weng, Hsing Yu; Hsu, Ming Jen; Chen, Chien Chih; Chen, Bing Chang; Hong, Chuang Ye; Teng, Che Ming; Pan, Shiow Lin; Chiu, Wen Ta; Lin, Chien Huang.

In: European Journal of Pharmacology, Vol. 698, No. 1-3, 05.01.2013, p. 103-109.

Research output: Contribution to journalArticle

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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.",
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T1 - Denbinobin induces human glioblastoma multiforme cell apoptosis through the IKKα-Akt-FKHR signaling cascade

AU - Weng, Hsing Yu

AU - Hsu, Ming Jen

AU - Chen, Chien Chih

AU - Chen, Bing Chang

AU - Hong, Chuang Ye

AU - Teng, Che Ming

AU - Pan, Shiow Lin

AU - Chiu, Wen Ta

AU - Lin, Chien Huang

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