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Zerumbone suppresses IKKα, Akt, and FOXO1 activation, resulting in apoptosis of GBM 8401 cells

Hsing-Yu Weng12, Ming-Jen Hsu3, Ching-Chung Wang4, Bing-Chang Chen5, Chuang-Ye Hong6, Mei-Chieh Chen7, Wen-Ta Chiu1* and Chien-Huang Lin7*

Author Affiliations

1 Graduate Institute of Clinical Medicine, Taipei Medical University, No.250, Wu-Hsing Street, 11031, Taipei, Taiwan

2 Department of Neurology, Wan Fang Hospital, Taipei Medical University, No.111, Sec. 3, Hsing-Long Road, Taipei, 11696, Taiwan

3 Department of Pharmacology, College of Medicine, Taipei Medical University, No. 250, Wu-Hsing Street, 11031, Taipei, Taiwan

4 Graduate Institute of Pharmacognosy, College of Pharmacy, Taipei Medical University, No. 250, Wu-Hsing Street, 11031, Taipei, Taiwan

5 School of Respiratory therapy, College of Medicine, Taipei Medical University, No. 250, Wu-Hsing Street, 11031, Taipei, Taiwan

6 School of Medicine, College of Medicine, Taipei Medical University, No. 250, Wu-Hsing Street, 11031, Taipei, Taiwan

7 Graduate Institute of Medical Science, College of Medicine, Taipei Medical University, No.250, Wu-Hsing Street, 11031, Taipei, Taiwan

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Journal of Biomedical Science 2012, 19:86  doi:10.1186/1423-0127-19-86

Published: 5 October 2012

Abstract

Background

Zerumbone, a sesquiterpene compound isolated from subtropical ginger, Zingiber zerumbet Smith, has been documented to exert antitumoral and anti- inflammatory activities. In this study, we demonstrate that zerumbone induces apoptosis in human glioblastoma multiforme (GBM8401) cells and investigate the apoptotic mechanism.

Methods

We added a caspase inhibitor and transfected wild-type (WT) IKK and Akt into GBM 8401 cells, and measured cell viability and apoptosis by MTT assay and flow cytometry. By western blotting, we evaluated activation of caspase-3, dephosphorylation of IKK, Akt, FOXO1 with time, and change of IKK, Akt, and FOXO1 phosphorylation after transfection of WT IKK and Akt.

Results

Zerumbone (10∽50 μM) induced death of GBM8401 cells in a dose-dependent manner. Flow cytometry studies showed that zerumbone increased the percentage of apoptotic GBM cells. Zerumbone also caused caspase-3 activation and poly (ADP-ribose) polymerase (PARP) production. N-benzyloxycarbonyl -Val-Ala-Asp- fluoromethylketone (zVAD-fmk), a broad-spectrum caspase inhibitor, hindered zerumbone-induced cell death. Transfection of GBM 8401 cells with WT IKKα inhibited zerumbone-induced apoptosis, and zerumbone significantly decreased IKKα phosphorylation levels in a time-dependent manner. Similarly, transfection of GBM8401 cells with Akt suppressed zerumbone-induced apoptosis, and zerumbone also diminished Akt phosphorylation levels remarkably and time-dependently. Moreover, transfection of GBM8401 cells with WT IKKα reduced the zerumbone-induced decrease in Akt and FOXO1 phosphorylation. However, transfection with WT Akt decreased FOXO1, but not IKKα, phosphorylation.

Conclusion

The results suggest that inactivation of IKKα, followed by Akt and FOXO1 phosphorylation and caspase-3 activation, contributes to zerumbone-induced GBM cell apoptosis.

Keywords:
Zerumbone; IKK; Akt; FOXO1; Glioblastoma multiforme