Premium
Honokiol inhibits gastric tumourigenesis by activation of 15‐lipoxygenase‐1 and consequent inhibition of peroxisome proliferator‐activated receptor‐γ and COX‐2‐dependent signals
Author(s) -
Liu Shing Hwa,
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
Publication year - 2010
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2010.00804.x
Subject(s) - honokiol , peroxisome proliferator activated receptor , small interfering rna , apoptosis , cancer research , chemistry , cancer cell , cell culture , receptor , microbiology and biotechnology , biology , cancer , transfection , biochemistry , gene , genetics
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.