title: COX2 inhibitor NS398 reduces HT-29 cell invasiveness by modulating signaling pathways mediated by EGFR and HIF1-α.
abstract: BACKGROUND
  Signals from the tumor microenvironment (hypoxia, growth factors) are known to induce an invasive phenotype. Cyclooxygenase-2 (COX2) overexpression, involved in colorectal carcinoma (CRC) progression, is also associated with epidermal growth factor receptor (EGFR) up-regulation. The present study investigated whether inhibition of COX2 may affect, under normoxia and hypoxia, EGF-induced cell proliferation and invasiveness by using immunoblotting, trypan blue assay, Boyden chamber assay and zymography.
  
  
  RESULTS
  The proliferative and invasive activity of HT-29 cells was enhanced under hypoxia. COX2 expression was increased after epidermal growth factor (EGF) stimulation under both hypoxia and normoxia, expression that was efficiently reduced by the COX2 inhibitor NS398. Under normoxia, NS398 reduced signalling pathways induced by EGF [phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT), extracellular-signal-regulated kinases (ERKs)], while under hypoxia, EGF stimulation and NS398 treatment was associated with HIF-1α expression. Under both conditions, NS398 was able to inhibit cell invasiveness and matrix-metalloproteinase-2 release.
  
  
  CONCLUSIONS
  COX2 inhibition can contribute to reducing cell aggressiveness through interfering with EGF- and hypoxia-mediated signaling.
authors.affiliation: Department of Clinical and Biological Sciences, Unit of Experimental Medicine and Clinical Pathology, University of Turin, C. Raffaello, 30 - 10125 Turin, Italy. claudia.bocca@unito.it.
authors.forename: Claudia
authors.initials: C
authors.lastname: Bocca
authors.forename: Francesca
authors.initials: F
authors.lastname: Bozzo
authors.forename: Antonella
authors.initials: A
authors.lastname: Miglietta
mesh_terms: D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D058750:Epithelial-Mesenchymal Transition; D066246:ErbB Receptors / Q000378:metabolism*; D019073:HT29 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D009578:Nitrobenzenes / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009578:Nitrobenzenes; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D004815:Epidermal Growth Factor; D066246:ErbB Receptors
keywords: COX2; EGFR; HT-29; hypoxia; invasiveness