title: EGFR signaling is required for TGF-beta 1 mediated COX-2 induction in human bronchial epithelial cells.
abstract: Cyclooxygenase-2 (COX-2) is a key enzyme in the production of prostaglandins and thromboxanes from free arachidonic acid. Increasing evidence suggests that COX-2 plays a role in tumorigenesis. A variety of stimuli induce COX-2 and it is overexpressed in many tumors, including non-small cell lung cancer (NSCLC). We studied the regulation of COX-2 expression in immortalized human bronchial epithelial cells (HBECs) by transforming growth factor-beta1 (TGF-beta1) and epidermal growth factor (EGF) because these two growth factors are present in both the pulmonary milieu of those at risk for lung cancer as well as in the tumor microenvironment. EGF significantly enhanced TGF-beta1-mediated induction of COX-2 and corresponding prostaglandin E2 (PGE2) production. TGF-beta1 and EGF induced COX-2 at the transcriptional and post-transcriptional levels. EGF receptor (EGFR) inhibition, neutralizing antibody against amphiregulin, or mitogen-activated protein kinase kinase (MEK) inhibition blocked TGF-beta1-mediated COX-2 induction. COX-2 induction by TGF-beta1 depended upon Smad3 signaling and required the activity of EGFR or its downstream mediators. Autocrine amphiregulin signaling maintains EGFR in a constitutively active state in HBECs, allowing for COX-2 induction by TGF-beta1. Thus, EGFR ligands, which are abundant in the pulmonary microenvironment of those at risk for lung cancer, potentiate and are required for COX-2 induction by TGF-beta1 in HBEC. These findings emphasize the central role of EGFR signaling in COX-2 induction by TGF-beta1 and suggest that inhibition of EGFR signaling should be investigated further for lung cancer prevention.
authors.affiliation: Lung Cancer Research Program, Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California 90095, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Liu
authors.forename: Seok-Chul
authors.initials: SC
authors.lastname: Yang
authors.forename: Sherven
authors.initials: S
authors.lastname: Sharma
authors.forename: Jie
authors.initials: J
authors.lastname: Luo
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Cui
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Peebles
authors.forename: Min
authors.initials: M
authors.lastname: Huang
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Sato
authors.forename: Ruben D
authors.initials: RD
authors.lastname: Ramirez
authors.forename: Jerry W
authors.initials: JW
authors.lastname: Shay
authors.forename: John D
authors.initials: JD
authors.lastname: Minna
authors.forename: Steven M
authors.initials: SM
authors.lastname: Dubinett
mesh_terms: D001980:Bronchi / Q000166:cytology* / Q000201:enzymology; D002461:Cell Line, Transformed; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D015232:Dinoprostone / Q000096:biosynthesis; D004790:Enzyme Induction / Q000502:physiology; D066246:ErbB Receptors / Q000502:physiology*; D006801:Humans; D020545:Respiratory Mucosa / Q000166:cytology / Q000201:enzymology*; D015398:Signal Transduction / Q000502:physiology*; D053773:Transforming Growth Factor beta1 / Q000502:physiology*
chemical_list: D053773:Transforming Growth Factor beta1; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D066246:ErbB Receptors; D015232:Dinoprostone