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Regulation of cyclooxygenase-2 (COX-2) expression in human pancreatic carcinoma cells by the insulin-like growth factor-I receptor (IGF-IR) system.

Stoeltzing O, Liu W, Fan F, Wagner C, Stengel K, Somcio RJ, Reinmuth N, Parikh AA, Hicklin DJ, Ellis LM
Cancer Lett. 2007 258 (2): 291-300

PMID: 17950526 · PMCID: PMC2147684 · DOI:10.1016/j.canlet.2007.09.009

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.

MeSH Terms (24)

Adaptor Proteins, Signal Transducing Blotting, Northern Blotting, Western Cell Line, Tumor Cyclooxygenase 2 Enzyme Inhibitors Gene Expression Regulation, Enzymologic Gene Expression Regulation, Neoplastic Humans Hypoxia-Inducible Factor 1, alpha Subunit Insulin-Like Growth Factor I Insulin Receptor Substrate Proteins Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3 Models, Biological Pancreatic Neoplasms Phosphatidylinositol 3-Kinases Phosphoinositide-3 Kinase Inhibitors Phosphorylation Receptor, IGF Type 1 RNA, Messenger RNA, Small Interfering Signal Transduction Transfection

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