Honokiol inhibits gastric tumourigenesis by activation of 15-lipoxygenase-1 and consequent inhibition of peroxisome proliferator-activated receptor-γ and COX-2-dependent signals
Journal
British Journal of Pharmacology
Journal Volume
160
Journal Issue
8
Pages
1963-1972
Date Issued
2010
Author(s)
Shen, Chin Chang
Yi, Yu Chiao
Tsai, Jaw Ji
Wang, Chih Chien
Chueh, Ju Ting
Lin, Keh Liang
Lee, Tso Ching
Pan, Hung Chuan
Sheu, Meei Ling
Abstract
Background and purpose: Peroxisome proliferator-activated receptor-γ (PPAR-γ), COX-2 and 15-lipoxygenase (LOX)-1 have been shown to be involved in tumour growth. However, the roles of PPAR-γ, 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-γ and COX-2 signalling during gastric tumourigenesis. Experimental approach: 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-γ 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. Key results: PPAR-γ and COX-2 proteins were highly expressed in gastric cancer cells. Inhibitors, or siRNA for COX-2 or PPAR-γ, significantly decreased cell viability. Honokiol markedly inhibited PPAR-γ 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-γ and COX-2, and cell apoptosis. 15-LOX-1 was markedly induced in tumours of xenograft mice treated with honokiol. Conclusions and implications: These findings suggest that induction of 15-LOX-1-mediated down-regulation of a PPAR-γ and COX-2 pathway by honokiol may be a promising therapeutic strategy for gastric cancer. ? 2010 The British Pharmacological Society.
Subjects
15-LOX-1; calpain; COX-2; gastric tumourigenesis; honokiol; PPAR-γ
SDGs
Other Subjects
arachidonate 15 lipoxygenase; arachidonate 15 lipoxygenase 1; coriolic acid; cyclooxygenase 2; honokiol; linoleic acid; peroxisome proliferator activated receptor gamma; small interfering RNA; unclassified drug; 13-hydroxy-9,11-octadecadienoic acid; ALOX15 protein, human; antineoplastic agent; arachidonate 15 lipoxygenase; biphenyl derivative; cyclooxygenase 2; honokiol; lignan; linoleic acid; peroxisome proliferator activated receptor gamma; prostaglandin synthase inhibitor; PTGS2 protein, human; animal experiment; animal model; apoptosis; article; cancer cell culture; cancer inhibition; cell death; cell viability; controlled study; down regulation; enzyme activation; enzyme induction; enzyme inhibition; gene expression; human; human tissue; immunohistochemistry; in vivo study; lipid metabolism; male; mouse; nonhuman; priority journal; protein expression; reverse transcription polymerase chain reaction; signal transduction; stomach cancer; Western blotting; xenograft; animal; Bagg albino mouse; cell survival; dose response; drug effects; drug screening; enzymology; gene expression regulation; genetics; metabolism; nude mouse; pathology; RNA interference; Stomach Neoplasms; time; tumor cell line; tumor volume; Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Arachidonate 15-Lipoxygenase; Biphenyl Compounds; Blotting, Western; Cell Line, Tumor; Cell Survival; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Dose-Response Relationship, Drug; Enzyme Activation; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Humans; Lignans; Linoleic Acids; Male; Mice; Mice, Inbred BALB C; Mice, Nude; PPAR gamma; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Signal Transduction; Stomach Neoplasms; Time Factors; Tumor Burden; Xenograft Model Antitumor Assays
Type
journal article