Prostaglandin E2 Enhances Pancreatic Cancer Invasiveness through an Ets-1-Dependent Induction of Matrix Metalloproteinase-2

Ito, Hiromichi; Duxbury, Mark; Benoît, Éric; Clancy, Thomas E.; Zinner, Michael J.; Ashley, Stanley W.; Whang, Edward E.

doi:10.1158/0008-5472.can-04-1177

Cited by 121 publications

(84 citation statements)

References 46 publications

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“…Both cyclooxygenases (PTGS1 and PTGS2) are identified as overexpressed in PDAC by our meta-analysis (Figure 3). These findings underline the importance of the cyclooxygenase system for the PDAC development since it has been demonstrated that inhibition of PTGS2 leads to reduced invasiveness of pancreatic cancer cells (Ito et al, 2004). Taken together, we were able to identify an overexpression of genes associated with CAM-DR and with increased invasiveness and metastasis in primary pancreatic adenocarcinoma.…”

Section: Discussionsupporting

confidence: 73%

Meta-analysis of microarray data on pancreatic cancer defines a set of commonly dysregulated genes

Boriss²,

et al. 2005

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Pancreatic ductal adenocarcinoma is the eighth most common cancer with the lowest overall 5-year relative survival rate of any tumor type today. Expression profiling using microarrays has been widely used to identify genes associated with pancreatic cancer development. To extract maximum value from the available gene expression data, we applied a meta-analysis to search for commonly differentially expressed genes in pancreatic ductal adenocarcinoma. We obtained data sets from four different gene expression studies on pancreatic cancer. We selected a consensus set of 2984 genes measured in all four studies and applied a meta-analysis approach to evaluate the combined data. Of the genes identified as differentially expressed, several were validated using RT-PCR and immunohistochemistry. Additionally, we used a class discovery algorithm to identify a gene expression signature. Our meta-analysis revealed that the pancreatic cancer gene expression data sets shared a significant number of up-and downregulated genes, independent of the technology used. This interstudy crossvalidation approach generated a set of 568 genes that were consistently and significantly dysregulated in pancreatic cancer. Of these, 364 (64.1%) were upregulated and 204 (35.9%) were downregulated in pancreatic cancer. Only 127 (22%) were described in the published individual analyses. Functional annotation of the genes revealed that genes presumably associated with the cell adhesionmediated drug resistance pathway are frequently overexpressed in pancreatic cancer. Meta-analysis is an important tool for the identification and validation of differentially expressed genes. These could represent good candidates for novel diagnostic and therapeutic approaches to pancreatic cancer.

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Section: Discussionsupporting

confidence: 73%

Meta-analysis of microarray data on pancreatic cancer defines a set of commonly dysregulated genes

Boriss²,

et al. 2005

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“…Until recently, the mode of action of NSAID was thought to be solely through inhibition of Cox, which, along with its products such as prostaglandin E 2 , is up-regulated in tumors and enhances the invasion of cancer cells via matrix metalloproteinase-2 (MMP-2; ref. 13). However, the chemopreventive effects of these compounds may also occur, in part, through gene modulation.…”

Section: Introductionmentioning

confidence: 99%

The anti-invasive activity of cyclooxygenase inhibitors is regulated by the transcription factor ATF3 (activating transcription factor 3)

Bottone

Moon

Kim

et al. 2005

Molecular Cancer Therapeutics

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We previously showed that nonsteroidal anti-inflammatory drugs (NSAID) such as sulindac sulfide, which has chemopreventive activity, modulate the expression of several genes detected by microarray analysis. Activating transcription factor 3 (ATF3) was selected for further study because it is a transcription factor involved in cell proliferation, apoptosis, and invasion, and its expression is repressed in human colorectal tumors as compared with normal adjacent tissue. In this report, we show that ATF3 mRNA and protein expression are up-regulated in HCT-116 human colorectal cancer cells following treatment with NSAIDs, troglitazone, diallyl disulfide, and resveratrol. To ascertain the biological significance of ATF3, we overexpressed full-length ATF3 protein in the sense and antisense orientations. Overexpression of ATF3 in the sense orientation decreased focus formation in vitro and reduced the size of mouse tumor xenografts by 54% in vivo. Conversely, overexpression of antisense ATF3 was protumorigenic in vitro, however, not in vivo. ATF3 in the sense orientation did not modulate apoptosis, indicating another mechanism is involved. With microarray analysis, several genes relating to invasion and metastasis were identified by ATF3 overexpression and were confirmed by real-time reverse transcription-PCR, and several of these genes were modulated by sulindac sulfide, which inhibited invasion in these cells. Furthermore, overexpression of ATF3 inhibited invasion to a similar degree as sulindac sulfide treatment, whereas antisense ATF3 increased invasion. In conclusion, ATF3 represents a novel mechanism in which NSAIDs exert their anti-invasive activity, thereby linking ATF3 and its gene regulatory activity to the biological activity of these compounds. [Mol Cancer Ther 2005;4(5):693 -703]

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“…Ets-1 is one of transcription factors activated by ERK1/2 signaling pathway. 27) The correlation between MMP-7 and Ets-1 expression has been observed in HCC tissues, and the forced expression of Ets-1 significiantly induced MMP-7 expression in HepG2 cells. 18) We are currently investigating whether Ets-1 is associated with isofraxidin-mediated inhibition of MMP-7 expression.…”

Section: Discussionmentioning

confidence: 95%

Isofraxidin, a Coumarin Component from Acanthopanax senticosus, Inhibits Matrix Metalloproteinase-7 Expression and Cell Invasion of Human Hepatoma Cells

Yamazaki

Tokiwa

2010

Biological & Pharmaceutical Bulletin

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Invasion and metastasis of cancer cells are the major causes of high motality in cancer patients. Matrix metalloproteinases (MMPs) are zinc-dependent proteolytic enzymes capable of degrading the components of extracellular matrix (ECM), including type IV collagen, gelatin and fibronectin. Cancer cells destruct surrounding tissues by enzymatic action of MMPs, leading to cancer invasion and metastasis. Among several MMPs, MMP-2, -7 and -9 are considered to be involved in cancer invasion and metastasis. In particular, MMP-7 is frequently found to overexpress in the invasive edge of cancer cells and play important roles in invasion or metastasis of digestive cancer. 1,2) Recently, the attempt to search for MMP inhibitors from plants is being performed, and several investigators have reported the inhibitory effects of epigallocatechin, 3) caffeic acid, 4) and proanthocyanin 5) on gene expression or enzymatic activity of MMP-2 and -9. However, except for the papers by Kawabata et al.,[6][7][8] little attention has been given to the development of MMP-7 inhibitors.Isofraxidin occurs in a variety of plants including Acansopanax senticosus HARMs (Japanese name: Ezoukogi). As the major compounds of Acanthopanax senticosus, eleutheroside B, B1, E, isofraxidin, and chlorogenic acid have been identified, isolated, and reported to possess several biological activities, such as anti-stress, anti-fatigue, antigastric ulcer, anti-depressive, immuno-enhancing and antiinflammatory effects. [9][10][11][12][13][14][15][16] We previously examined the effect of isofraxidin on the expression of inflammatory mediator cyclooxygenase-2 (COX-2) mRNA and found inhibitory effects at a significant level on human synovial sarcoma cell line SW982 cells. [11][12][13][14][15][16] In this study, we investigated isofraxidin in its anti-tumor effects on human hepatoma cell lines in cellular and molecular terms. MATERIALS AND METHODSCell Culture Human hepatoma cell lines HuH-7, HepG2 and HLE and a human lung fibroblast cell line IMR90 were obtained from Japanese Collection of Research Bioresources (JCRB). Cells were grown in RPMI-1640 culture medium supplemented with 10% fetal bovine serum (FBS), 100 U/ml penicillin, and 100 mg/ml streptomycin at 37°C in a humidified atmosphere of 5% CO 2 and 95% air.Phenolic Compounds Isofraxidin was purchased from Wako Pure Chemical Industries, Ltd. (Osaka, Japan). Eleutheroside E was purchased from Phytochem Referenzsubstanzen GbRmb (Ichenhausen, Germany). The compounds were added to the culture medium at appropriate concentrations as a dimethylsulfoxide (DMSO) solution (the final DMSO concentration was 0.5% in all cultures), and the same amount of vehicle was added to the control cultures.3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium Bromide (MTT) Assay For cell attachment study, cells were plated in 96-well plates at 3.0ϫ10 4 cells/cm 2 (low cell density) in 0.1 ml of serum-free RPMI-1640 medium containing or not containing isofraxidin and incubated for 24 h. For cell growth study, cells were plated i...

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Prostaglandin E2 Enhances Pancreatic Cancer Invasiveness through an Ets-1-Dependent Induction of Matrix Metalloproteinase-2

Cited by 121 publications

References 46 publications

Meta-analysis of microarray data on pancreatic cancer defines a set of commonly dysregulated genes

Meta-analysis of microarray data on pancreatic cancer defines a set of commonly dysregulated genes

The anti-invasive activity of cyclooxygenase inhibitors is regulated by the transcription factor ATF3 (activating transcription factor 3)

Isofraxidin, a Coumarin Component from Acanthopanax senticosus, Inhibits Matrix Metalloproteinase-7 Expression and Cell Invasion of Human Hepatoma Cells

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