title: Dimerumic acid inhibits SW620 cell invasion by attenuating H₂O₂-mediated MMP-7 expression via JNK/C-Jun and ERK/C-Fos activation in an AP-1-dependent manner.
abstract: Reactive oxygen species (ROS) such as hydrogen peroxide (H₂O₂) in the tumor microenvironment play important roles in tumor invasion and metastasis. Recently, ROS have been reported to cause a significant increase in the production and expression of matrix metalloproteinase (MMP)-7, which is closely correlated with metastatic colorectal cancer. The present study was undertaken to evaluate the scavenging activity of dimerumic acid (DMA) for H₂O₂ isolated from Monascus-fermented rice to investigate the inhibitory effects of DMA on the invasive potential of SW620 human colon cancer cells, and to explore the mechanisms underlying both these phenomena. Our results showed that increased MMP-7 expression due to H₂O₂ exposure was mediated by activation of mitogen-activated protein kinases (MAPKs) such as Jun N-terminal kinase (JNK), extracellular-regulated kinase (ERK), and p38 kinase. DMA pretreatment suppressed activation of H₂O₂-mediated MAPK pathways and cell invasion. Moreover, H₂O₂-triggered MMP-7 production was demonstrated via JNK/c-Jun and ERK/c-Fos activation in an activating protein 1 (AP-1)-dependent manner. Taken together, these results suggest that DMA suppresses H₂O₂-induced cell invasion by inhibiting AP-1-mediated MMP-7 gene transcription via the JNK/c-Jun and ERK/c-Fos signaling pathways in SW620 human colon cancer cells. Our data suggest that DMA may be useful in minimizing the development of colorectal metastasis. In the future, DMA supplementation may be a beneficial antioxidant to enhance surgical outcomes.
authors.affiliation: Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Bing-Ying
authors.initials: BY
authors.lastname: Ho
authors.forename: Yao-Ming
authors.initials: YM
authors.lastname: Wu
authors.forename: King-Jen
authors.initials: KJ
authors.lastname: Chang
authors.forename: Tzu-Ming
authors.initials: TM
authors.lastname: Pan
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy; D000818:Animals; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy; D054659:Diketopiperazines / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D004354:Drug Screening Assays, Antitumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000008:administration & dosage / Q000378:metabolism*; D006877:Hydroxamic Acids / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D020783:Matrix Metalloproteinase 7 / Q000378:metabolism*; D032741:Monascus; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D012275:Oryza / Q000737:chemistry / Q000382:microbiology; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D054659:Diketopiperazines; D006877:Hydroxamic Acids; D018808:Transcription Factor AP-1; C552122:dimerumic acid; D006861:Hydrogen Peroxide; C060932:MMP7 protein, human; D020783:Matrix Metalloproteinase 7