title: Honokiol inhibits gastric tumourigenesis by activation of 15-lipoxygenase-1 and consequent inhibition of peroxisome proliferator-activated receptor-gamma and COX-2-dependent signals.
abstract: OBJECTIVE
  Peroxisome proliferator-activated receptor-gamma (PPAR-gamma), COX-2 and 15-lipoxygenase (LOX)-1 have been shown to be involved in tumour growth. However, the roles of PPAR-gamma, COX-2 or 15-LOX-1 in gastric tumourigenesis remain unclear. Here, we investigate the role of 15-LOX-1 induction by honokiol, a small-molecular weight natural product, in PPAR-gamma and COX-2 signalling during gastric tumourigenesis.
  
  
  METHODS
  Human gastric cancer cell lines (AGS, MKN45, N87 and SCM-1) were cultured with or without honokiol. Gene and protein expressions were analysed by RT-PCR and Western blotting respectively. Small interfering RNAs (siRNAs) for COX-2, PPAR-gamma and 15-LOX-1 were used to interfere with the expressions of these genes. A xenograft gastric tumour model in mouse was used for in vivo study.
  
  
  RESULTS
  PPAR-gamma and COX-2 proteins were highly expressed in gastric cancer cells. Inhibitors, or siRNA for COX-2 or PPAR-gamma, significantly decreased cell viability. Honokiol markedly inhibited PPAR-gamma and COX-2 expressions in gastric cancer cells and tumours of xenograft mice, and induced apoptosis and cell death. Honokiol markedly activated cellular 15-LOX-1 expression and 13-S-hydroxyoctadecadienoic acid (a primary product of 15-LOX-1 metabolism of linoleic acid) production. 15-LOX-1 siRNA could reverse the honokiol-induced down-regulation of PPAR-gamma and COX-2, and cell apoptosis. 15-LOX-1 was markedly induced in tumours of xenograft mice treated with honokiol.
  
  
  CONCLUSIONS
  These findings suggest that induction of 15-LOX-1-mediated down-regulation of a PPAR-gamma and COX-2 pathway by honokiol may be a promising therapeutic strategy for gastric cancer.
authors.affiliation: Institute of Toxicology, Taipei, Taiwan.
authors.forename: Shing Hwa
authors.initials: SH
authors.lastname: Liu
authors.forename: Chin Chang
authors.initials: CC
authors.lastname: Shen
authors.forename: Yu Chiao
authors.initials: YC
authors.lastname: Yi
authors.forename: Jaw Ji
authors.initials: JJ
authors.lastname: Tsai
authors.forename: Chih Chien
authors.initials: CC
authors.lastname: Wang
authors.forename: Ju Ting
authors.initials: JT
authors.lastname: Chueh
authors.forename: Keh Liang
authors.initials: KL
authors.lastname: Lin
authors.forename: Tso Ching
authors.initials: TC
authors.lastname: Lee
authors.forename: Hung Chuan
authors.initials: HC
authors.lastname: Pan
authors.forename: Meei Ling
authors.initials: ML
authors.lastname: Sheu
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics / Q000378:metabolism*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017705:Lignans / Q000494:pharmacology*; D008041:Linoleic Acids / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000498:Allyl Compounds; D010636:Phenols
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D001093:Arachidonate 15-Lipoxygenase; D001713:Biphenyl Compounds; D051546:Cyclooxygenase 2; D016861:Cyclooxygenase Inhibitors; D017705:Lignans; D008041:Linoleic Acids; D047495:PPAR gamma; C005499:honokiol; D000498:Allyl Compounds; D010636:Phenols; C024348:13-hydroxy-9,11-octadecadienoic acid; C515716:ALOX15 protein, human; C496540:PTGS2 protein, human