Abstract
Both the insulin-like growth factor-I receptor (IGF-IR) and cyclooxygenase-2 (COX-2) are frequently overexpressed in pancreatic cancer. We hypothesized that IGF-IR is directly involved in induction of COX-2 and sought to investigate signaling pathways mediating this effect. Pancreatic cancer cells (L3.6pl) were stably transfected with a dominant-negative receptor (IGF-IR DN) construct or empty vector (pcDNA). Cells were stimulated with IGF-I to determine activated signaling intermediates and induction of COX-2. Signaling pathways mediating COX-2 induction were identified using signaling inhibitors. IGF-I up-regulated COX-2 selectively via the MAPK/(Erk-1/2) pathway. In addition, IGF-IR DN cells showed a marked decrease in constitutive COX-2 and a blunted response to IGF-I. Similarly, treatment with an anti-IGF-IR antibody effectively inhibited IGF-IR and MAPK/Erk activation and decreased COX-2 in parental cells. In conclusion, activation of IGF-IR mediates COX-2 expression in human pancreatic cancer cells.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / metabolism
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Blotting, Northern
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Blotting, Western
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Cell Line, Tumor
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Cyclooxygenase 2 / genetics*
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Cyclooxygenase 2 / metabolism
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Enzyme Inhibitors / pharmacology
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Gene Expression Regulation, Enzymologic / drug effects
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Gene Expression Regulation, Neoplastic / drug effects
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / genetics
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
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Insulin Receptor Substrate Proteins
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Insulin-Like Growth Factor I / pharmacology*
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Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 3 / metabolism
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Models, Biological
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Pancreatic Neoplasms / genetics
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Pancreatic Neoplasms / metabolism
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Pancreatic Neoplasms / pathology
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Phosphorylation / drug effects
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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RNA, Small Interfering / genetics
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Receptor, IGF Type 1 / genetics
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Receptor, IGF Type 1 / physiology*
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Signal Transduction / drug effects
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Transfection
Substances
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Adaptor Proteins, Signal Transducing
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Enzyme Inhibitors
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HIF1A protein, human
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Hypoxia-Inducible Factor 1, alpha Subunit
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IRS1 protein, human
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Insulin Receptor Substrate Proteins
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Phosphoinositide-3 Kinase Inhibitors
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RNA, Messenger
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RNA, Small Interfering
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Insulin-Like Growth Factor I
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Cyclooxygenase 2
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Receptor, IGF Type 1
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3