title: Nobiletin suppresses cell viability through AKT pathways in PC-3 and DU-145 prostate cancer cells.
abstract: BACKGROUND
  Nobiletin is a non-toxic dietary flavonoid that possesses anti-cancer properties. Nobiletin has been reported to reduce the risk of prostate cancer, but the mechanism is not well understood. In this study, we investigated the effects of nobiletin in prostate cancer cell lines PC-3 and DU-145.
  
  
  METHODS
  Nobiletin was isolated from a polymethoxy flavonoid mixture using HPLC, cell viability was analyzed with MTS-based assays. Protein expression was examined by ELISA and western blotting. Gene expression was examined by luciferase assay. And the pathways were examined by manipulating genetic components with plasmid transfection.
  
  
  RESULTS
  Data showed that nobiletin decreased cell viability in both prostate cell lines, with a greater reduction in viability in PC-3 cells. HIF-1α expression and AKT phosphorylation were decreased in both cell lines. The VEGF expression was inhibited in PC-3 but not DU-145 cells. cMyc expression was decreased in DU-145 cells. Nobiletin down-regulated NF-κB (p50) expression in nuclei of DU145 cells but not whole cells. It also suppressed NF-κB expression in both whole cells and nuclei of PC-3 cells. Increasing HIF-1α levels reversed nobiletin's inhibitory effects on VEGF expression, and up-regulating AKT levels reversed its inhibitory effects on HIF-1α expression. We speculate that AKT influences cell viability probably by its effect on NF-κB in both prostate cells. The effect of nobiletin on VEGF expression in PC-3 cell lines was through the AKT/HIF-1α pathway.
  
  
  CONCLUSIONS
  Taken together, our results show that nobiletin suppresses cell viability through AKT pathways, with a more profound effect against the more metastatic PC-3 line. Due to this enhanced action against a more malignant cell type, nobiletin may be used to improve prostate cancer survival rates.
authors.forename: Jianchu
authors.initials: J
authors.lastname: Chen
authors.forename: Ashley
authors.initials: A
authors.lastname: Creed
authors.forename: Allen Y
authors.initials: AY
authors.lastname: Chen
authors.forename: Haizhi
authors.initials: H
authors.lastname: Huang
authors.forename: Zhaoliang
authors.initials: Z
authors.lastname: Li
authors.forename: Gary O
authors.initials: GO
authors.lastname: Rankin
authors.forename: Xingqian
authors.initials: X
authors.lastname: Ye
authors.forename: Guihua
authors.initials: G
authors.lastname: Xu
authors.affiliation: College of Science, Technology and Mathematics, Alderson Broaddus University, Philippi, WV 26416, USA. chenyc@ab.edu.
authors.forename: Yi Charlie
authors.initials: YC
authors.lastname: Chen
mesh_terms: D015153:Blotting, Western; D045744:Cell Line, Tumor; D004797:Enzyme-Linked Immunosorbent Assay; D047309:Flavones / Q000502:physiology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D047309:Flavones; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016328:NF-kappa B; D016271:Proto-Oncogene Proteins c-myc; D042461:Vascular Endothelial Growth Factor A; C008661:nobiletin; D051057:Proto-Oncogene Proteins c-akt