13-hydroxy-9-11-octadecadienoic-acid and Stomach-Neoplasms

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.. 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.. 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.. 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.

Topics: 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

It has been found that expression of 15-lipoxygenase-1 (15-LOX-1) and its main product, 13-S-hydroxyoctadecadienoic acid (13-S-HODE), are decreased in human colorectal and esophageal cancers and that non-steroidal anti-inflammatory drugs (NSAIDs) can therapeutically induce 15-LOX-1 expression to trigger apoptosis in those cancer cells. We found that a specific cyclooxygenase-2 (COX-2) inhibitor SC-236 similarly induced apoptosis in gastric cancer cells. In the present study, we tested whether SC-236 induced apoptosis through up-regulation of 15-LOX-1 in gastric cancer. We found that: (i) SC-236 inhibited growth of gastric cancer cells mainly by inducing apoptosis; (ii) SC-236 induced 15-LOX-1 expression and increased endogenous 13-S-HODE product, instead of 15-S-HETE during apoptosis; (iii) SC-236 did not affect expression of COX-1, COX-2, 5-LOX and 12-LOX; and (iv) 15-LOX-1 inhibition suppressed SC-236 induced apoptosis. These findings demonstrated that SC-236 induced apoptosis in gastric cancer cells via up-regulation of 15-LOX-1, and 13-S-HODE. These are potential and new targets for prevention and treatment of gastric cancer.

Topics: Apoptosis; Arachidonate 15-Lipoxygenase; Base Sequence; Caffeic Acids; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; DNA Primers; Isoenzymes; Linoleic Acids; Prostaglandin-Endoperoxide Synthases; Pyrazoles; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Stomach Neoplasms; Sulfonamides; Tumor Cells, Cultured