Abstract
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.
Highlights
Gastric cancer currently ranks second in global cancer mortality, with an estimated 990,000 new cases and 738,000 cancer deaths resulting worldwide annually, the incidence of PLOS ONE | DOI:10.1371/journal.pone.0124007 April 15, 2015Chrysin Inhibits Matrix metalloproteinase-9 (MMP-9) in Gastric Cancer Cells and analysis, decision to publish, or preparation of the manuscript
To investigate the suppressive effect of chrysin against the upregulation of matrix metalloproteinases (MMPs)-9, AGS cells pretreated with chrysin were incubated with phorbol-12-myristate 13-acetate (PMA), and gelatin zymography and reverse transcription-polymerase chain reaction (RT-PCR) analysis were performed
We hypothesized that the inhibition of chrysin against MMP-9 may be via suppression of MMP-9 expression
Summary
Gastric cancer currently ranks second in global cancer mortality, with an estimated 990,000 new cases and 738,000 cancer deaths resulting worldwide annually, the incidence of PLOS ONE | DOI:10.1371/journal.pone.0124007 April 15, 2015. It has been reported that overexpression of MMPs can increase tumor cell detachment and metastasis, which are associated with malignancy and poor clinical outcomes in various cancers including gastric cancer [9,10]. Kim et al discovered that silibinin inhibits PMA-induced MMP-9 expression through suppression of ERK phosphorylation in MCF-7 human breast cancer cells [11]. Khoi et al reported that (-)-Epigallocatechin-3-gallate blocks nicotine-induced MMP-9 expression and invasiveness through the suppression of NF-κB and AP-1 in endothelial ECV304 cells [12]. The inhibitory effects of chrysin on MMP-9, as well as the mechanism, have not been well studied, especially in gastric cancer cells. We investigated chrysin’s effects on PMA-induced MMP-9 expression in gastric cancer, and revealed its underlying mechanism
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