Abstract
Cyclooxygenase (COX)-2 and vascular endothelial growth factor (VEGF) are significantly associated with tumor growth and metastasis. Here we show that phorbol ester-mediated induction of VEGF and COX-2 expression in colon carcinoma cells is inhibited by 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)). This cyclopentenone was able to inhibit activator protein1 (AP-1)-dependent transcriptional induction of COX-2 and VEGF promoters induced by phorbol 12-myristate 13-acetate (PMA) or c-Jun overexpression. 15d-PGJ(2) interfered with at least two steps within the signaling pathway leading to AP-1 activation. First, 15d-PGJ(2) impaired AP-1 binding to a consensus DNA sequence. Second, 15d-PGJ(2) selectively inhibited c-Jun NH(2) terminal kinase (JNK) but not extracellular signal-regulated kinase or p38 mitogen-activated protein kinase activation induced by PMA. This led to a decreased ability of JNK to phosphorylate c-Jun and to activate its transactivating activity. Inhibition of AP-1 activation and COX-2 or VEGF transcriptional induction by this cyclopentenone was found to be independent of peroxisome proliferator-activated receptor-gamma (PPARgamma) because it was not affected by either expression of a dominant negative form of PPARgamma or the use of a PPARgamma antagonist. In contrast, we have found that the effects of 15d-PGJ(2) on AP-1 activation may occur through its ability to induce intracellular oxidative stress. The antioxidant N-acetylcysteine significantly reversed the inhibition by 15d-PGJ(2) of AP-1 activity and COX-2 or VEGF transcriptional induction. Together, these findings provide new insight into the antitumoral properties of 15d-PGJ(2) through the inhibition of the induction of AP-1-dependent genes involved in tumor progression, such as COX-2 and VEGF.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Survival / drug effects
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Colonic Neoplasms / genetics
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Colonic Neoplasms / metabolism*
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Colonic Neoplasms / pathology
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Consensus Sequence
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Cyclooxygenase 2
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Electrophoretic Mobility Shift Assay
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Enzyme Activation / drug effects
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Enzyme Inhibitors / pharmacology
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Genes, Dominant
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Genes, jun / physiology
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Humans
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Immunologic Factors / pharmacology
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Isoenzymes / antagonists & inhibitors
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Isoenzymes / metabolism*
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JNK Mitogen-Activated Protein Kinases*
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MAP Kinase Kinase 4
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Membrane Proteins
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Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinases / metabolism
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Oxidation-Reduction*
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Phosphorylation
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Prostaglandin D2 / analogs & derivatives
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Prostaglandin D2 / pharmacology*
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Prostaglandin-Endoperoxide Synthases / metabolism*
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Protein Binding
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Reactive Oxygen Species / metabolism
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Receptors, Cytoplasmic and Nuclear / genetics
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Receptors, Cytoplasmic and Nuclear / metabolism*
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Signal Transduction
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Tetradecanoylphorbol Acetate / pharmacology
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Transcription Factor AP-1 / antagonists & inhibitors*
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Transcription Factor AP-1 / metabolism
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Transcription, Genetic / drug effects
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Transcriptional Activation / drug effects
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Tumor Cells, Cultured
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Vascular Endothelial Growth Factor A / antagonists & inhibitors
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Vascular Endothelial Growth Factor A / metabolism*
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p38 Mitogen-Activated Protein Kinases
Substances
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15-deoxy-delta(12,14)-prostaglandin J2
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Enzyme Inhibitors
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Immunologic Factors
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Isoenzymes
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Membrane Proteins
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Reactive Oxygen Species
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Receptors, Cytoplasmic and Nuclear
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Transcription Factor AP-1
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Transcription Factors
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Vascular Endothelial Growth Factor A
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Cyclooxygenase 2
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PTGS2 protein, human
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Prostaglandin-Endoperoxide Synthases
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 4
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Mitogen-Activated Protein Kinase Kinases
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Tetradecanoylphorbol Acetate
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Prostaglandin D2