Abstract
Nonsteroidal anti-inflammatory drugs reduce the risk of colon cancer and this effect is mediated in part through inhibition of type 2 prostaglandin endoperoxide synthase/ cyclo-oxygenase (COX-2). In the present study, we demonstrate that COX-2 expression and PGE2 synthesis are up-regulated by an IGF-II/IGF-I receptor autocrine pathway in Caco-2 colon carcinoma cells. COX-2 mRNA and PGE2 levels are higher in proliferating cells compared with post-confluent differentiated cells and in cells that constitutively overexpress IGF-II. Up-regulation of COX-2 expression by IGF-II is mediated through activation of IGF-I receptor because: (i) treatment of Caco-2 cells with a blocking antibody to the IGF-I receptor inhibits COX-2 mRNA expression; (ii) transfection of Caco-2 cells with a dominant negative IGF-I receptor reduces COX-2 expression and activity. Also, the blockade of the PI3-kinase, that mediates the proliferative effect of IGF-I receptor in Caco-2 cells, inhibits IGF-II-dependent COX-2 up-regulation and PGE2 synthesis. Moreover, COX-2 expression and activity inversely correlate with the increase of apoptosis in parental, IGF-II and dominant-negative IGF-I receptor transfected cells. This study suggests that induction of proliferation and tumor progression of colon cancer cells by the IGF-II/IGF-I receptor pathway may depend on the activation of COX-2-related events.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology
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Antibodies, Monoclonal / pharmacology
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Apoptosis / drug effects
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Apoptosis / physiology
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Caco-2 Cells / enzymology
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Caco-2 Cells / metabolism*
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Cell Division / physiology
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Cyclooxygenase 2
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Cyclooxygenase 2 Inhibitors
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Cyclooxygenase Inhibitors / pharmacology
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Dinoprostone / biosynthesis*
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Disease Progression
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Humans
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Insulin-Like Growth Factor II / antagonists & inhibitors
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Insulin-Like Growth Factor II / biosynthesis
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Insulin-Like Growth Factor II / physiology*
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Isoenzymes / biosynthesis*
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Isoenzymes / genetics
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Isoenzymes / metabolism
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MAP Kinase Signaling System / physiology
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Membrane Proteins
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Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
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Nitrobenzenes / pharmacology
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Phosphoinositide-3 Kinase Inhibitors
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Prostaglandin-Endoperoxide Synthases / biosynthesis*
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Prostaglandin-Endoperoxide Synthases / genetics
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Prostaglandin-Endoperoxide Synthases / metabolism
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RNA, Messenger / biosynthesis*
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RNA, Messenger / genetics
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Receptor, IGF Type 1 / antagonists & inhibitors
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Receptor, IGF Type 1 / genetics
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Receptor, IGF Type 1 / physiology*
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Signal Transduction / physiology
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Sulfonamides / pharmacology
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Transfection
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Up-Regulation / physiology
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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Antibodies, Monoclonal
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Cyclooxygenase 2 Inhibitors
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Cyclooxygenase Inhibitors
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Isoenzymes
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Membrane Proteins
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Nitrobenzenes
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Phosphoinositide-3 Kinase Inhibitors
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RNA, Messenger
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Sulfonamides
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N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide
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Insulin-Like Growth Factor II
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Cyclooxygenase 2
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PTGS2 protein, human
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Prostaglandin-Endoperoxide Synthases
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Receptor, IGF Type 1
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Mitogen-Activated Protein Kinase Kinases
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Dinoprostone