Journal Article

Chrysin Inhibits Tumor Promoter-Induced MMP-9 Expression by Blocking AP-1 via Suppression of ERK and JNK Pathways in Gastric Cancer Cells

Xia, Yong, Khoi, Pham Ngoc, Kim, Kyung Keun, Lian, Sen, Chay, Kee Oh, Do Jung, Young, Joo, Young Eun, Yoon, Hyun Joong

2015

Overview

Cell invasion is a crucial mechanism of cancer metastasis and malignancy. Matrix metalloproteinase-9 (MMP-9) is an important proteolytic enzyme involved in the cancer cell invasion process. High expression levels of MMP-9 in gastric cancer positively correlate with tumor aggressiveness and have a significant negative correlation with patients' survival times. Recently, mechanisms suppressing MMP-9 by phytochemicals have become increasingly investigated. Chrysin, a naturally occurring chemical in plants, has been reported to suppress tumor metastasis. However, the effects of chrysin on MMP-9 expression in gastric cancer have not been well studied. In the present study, we tested the effects of chrysin on MMP-9 expression in gastric cancer cells, and determined its underlying mechanism. We examined the effects of chrysin on MMP-9 expression and activity via RT-PCR, zymography, promoter study, and western blotting in human gastric cancer AGS cells. Chrysin inhibited phorbol-12-myristate 13-acetate (PMA)-induced MMP-9 expression in a dose-dependent manner. Using AP-1 decoy oligodeoxynucleotides, we confirmed that AP-1 was the crucial transcriptional factor for MMP-9 expression. Chrysin blocked AP-1 via suppression of the phosphorylation of c-Jun and c-Fos through blocking the JNK1/2 and ERK1/2 pathways. Furthermore, AGS cells pretreated with PMA showed markedly enhanced invasiveness, which was partially abrogated by chrysin and MMP-9 antibody. Our results suggest that chrysin may exert at least part of its anticancer effect by controlling MMP-9 expression through suppression of AP-1 activity via a block of the JNK1/2 and ERK1/2 signaling pathways in gastric cancer AGS cells.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Acetic acid / Angiogenesis / Antibodies - pharmacology / Anticancer properties / Antineoplastic Agents, Phytogenic - pharmacology / Blocking / Breast cancer / c-Fos protein / c-Jun protein / Cancer / Cancer cells / Cancer therapies / Cancer treatment / Cell Line, Tumor / Cell Movement - drug effects / Dose-Response Relationship, Drug / Enzymes / Epithelial Cells - drug effects / Epithelial Cells - metabolism / Epithelial Cells - pathology / Extracellular signal-regulated kinase / Flavonoids - pharmacology / Fos protein / Gastric cancer / Gastric Mucosa - metabolism / Gelatinase B / Gene expression / Gene Expression Regulation, Neoplastic / Humans / Invasiveness / Kinases / Malignancy / Matrix metalloproteinase / Matrix Metalloproteinase 9 - genetics / Matrix Metalloproteinase 9 - metabolism / Medical schools / Metalloproteinase / Metastases / Metastasis / Mitogen-Activated Protein Kinase 1 - antagonists & inhibitors / Mitogen-Activated Protein Kinase 1 - genetics / Mitogen-Activated Protein Kinase 1 - metabolism / Mitogen-Activated Protein Kinase 3 - antagonists & inhibitors / Mitogen-Activated Protein Kinase 3 - genetics / Mitogen-Activated Protein Kinase 3 - metabolism / Mitogen-Activated Protein Kinase 8 - antagonists & inhibitors / Mitogen-Activated Protein Kinase 8 - genetics / Mitogen-Activated Protein Kinase 8 - metabolism / Mitogen-Activated Protein Kinase 9 - antagonists & inhibitors / Mitogen-Activated Protein Kinase 9 - genetics / Mitogen-Activated Protein Kinase 9 - metabolism / Oligodeoxynucleotides / Oligodeoxyribonucleotides - genetics / Oligodeoxyribonucleotides - metabolism / Oligonucleotides / Phosphorylation / Polymerase chain reaction / Proteolysis / Proto-Oncogene Proteins c-fos - genetics / Proto-Oncogene Proteins c-fos - metabolism / Signal Transduction / Signaling / Stomach - drug effects / Stomach - pathology / Stomach cancer / Tetradecanoylphorbol Acetate - antagonists & inhibitors / Tetradecanoylphorbol Acetate - pharmacology / Transcription Factor AP-1 - antagonists & inhibitors / Transcription Factor AP-1 - genetics / Transcription Factor AP-1 - metabolism / Transcription factors / Western blotting