title: Epidermal growth factor receptor reactivation induced by E-prostanoid-3 receptor- and tumor necrosis factor-alpha-converting enzyme-dependent feedback exaggerates interleukin-8 production in airway cancer (NCI-H292) cells.
abstract: Airway epithelial cancer cells produce increased amounts of the chemokine interleukin-8 (IL-8), inducing pro-tumor responses. Multiple stimuli induce airway epithelial IL-8 production epidermal growth factor receptor (EGFR) dependently, but the mechanisms that exaggerate IL-8 production in airway cancers remain unknown. Here we show that direct activation of EGFR (EGFR-P) by its ligand transforming growth factor (TGF)-alpha induces a second EGFR-P in human airway (NCI-H292) cancer cells but not in normal human bronchial epithelial (NHBE) cells, exaggerating IL-8 production in these cancer cells. The second EGFR-P in NCI-H292 cells was caused by metalloprotease TNF-alpha-converting enzyme (TACE)-dependent cleavage of EGFR pro-ligands and was responsible for most of the total IL-8 induced by TGF-alpha. In NCI-H292 cells, TGF-alpha induced cyclooxygenase (COX)-2-dependent prostaglandin (PG)E2 production and release. PGE2 increased the second EGFR-P and IL-8 production via binding to its Gi-protein-coupled E-prostanoid (EP)3 receptor. In NHBE cells, TGF-alpha-induced EGFR-P did not lead to PGE2 production or to a second EGFR-P, and less IL-8 was produced. Thus, we conclude that a positive feedback pathway involving COX-2/PGE2/EP3 receptor-dependent EGFR reactivation exaggerates IL-8 production in NCI-H292 cancer cells but not in NHBE (normal) cells.
authors.affiliation: Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA 94143-0130, USA. kimsui@ohsu.edu
authors.forename: Suil
authors.initials: S
authors.lastname: Kim
authors.forename: Courtney
authors.initials: C
authors.lastname: Lewis
authors.forename: Jay A
authors.initials: JA
authors.lastname: Nadel
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism*; D000072198:ADAM17 Protein; D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D001980:Bronchi / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D066246:ErbB Receptors / Q000378:metabolism*; D025461:Feedback, Physiological; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis*; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology*; D058308:Receptors, Prostaglandin E, EP3 Subtype / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D016209:Interleukin-8; D058308:Receptors, Prostaglandin E, EP3 Subtype; D066246:ErbB Receptors; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human