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 language | English |
|---|---|
| Pages (from-to) | 103-109 |
| Number of pages | 7 |
| Journal | European Journal of Pharmacology |
| Volume | 698 |
| Issue number | 1-3 |
| DOIs | |
| Publication status | Published - Jan 5 2013 |
Fingerprint
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 journal › Article
}
TY - JOUR
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
PY - 2013/1/5
Y1 - 2013/1/5
N2 - 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.
AB - 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.
KW - Akt
KW - Denbinobin
KW - FKHR
KW - Glioblastoma multiforme
KW - IKK
UR - http://www.scopus.com/inward/record.url?scp=84871920050&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84871920050&partnerID=8YFLogxK
U2 - 10.1016/j.ejphar.2012.10.029
DO - 10.1016/j.ejphar.2012.10.029
M3 - Article
C2 - 23123054
AN - SCOPUS:84871920050
VL - 698
SP - 103
EP - 109
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
SN - 0014-2999
IS - 1-3
ER -