title: Zerumbone suppresses IKKα, Akt, and FOXO1 activation, resulting in apoptosis of GBM 8401 cells.
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.
  
  
  CONCLUSIONS
  The results suggest that inactivation of IKKα, followed by Akt and FOXO1 phosphorylation and caspase-3 activation, contributes to zerumbone-induced GBM cell apoptosis.
authors.affiliation: Graduate Institute of Clinical Medicine, Taipei Medical University, No,250, Wu-Hsing Street, 11031 Taipei, Taiwan.
authors.forename: Hsing-Yu
authors.initials: HY
authors.lastname: Weng
authors.forename: Ming-Jen
authors.initials: MJ
authors.lastname: Hsu
authors.forename: Ching-Chung
authors.initials: CC
authors.lastname: Wang
authors.forename: Bing-Chang
authors.initials: BC
authors.lastname: Chen
authors.forename: Chuang-Ye
authors.initials: CY
authors.lastname: Hong
authors.forename: Mei-Chieh
authors.initials: MC
authors.lastname: Chen
authors.forename: Wen-Ta
authors.initials: WT
authors.lastname: Chiu
authors.forename: Chien-Huang
authors.initials: CH
authors.lastname: Lin
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020939:Zingiber officinale / Q000737:chemistry; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D012717:Sesquiterpenes / Q000737:chemistry / Q000494:pharmacology; D015398:Signal Transduction
chemical_list: C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D012717:Sesquiterpenes; C403304:zerumbone; D051058:Oncogene Protein v-akt; D051550:I-kappa B Kinase; D053148:Caspase 3