Kinin b2 receptor mediates induction of cyclooxygenase-2 and is overexpressed in head and neck squamous cell carcinomas.
Bradykinin has been shown to promote growth and migration of head and neck squamous cell carcinoma (HNSCC) cells via epidermal growth factor receptor (EGFR) transactivation. It has also been reported that bradykinin can cause the induction of cyclooxygenase-2 (COX-2), a protumorigenic enzyme, via the mitogen-activated protein kinase (MAPK) pathway in human airway cells. To determine whether COX-2 is up-regulated by bradykinin in HNSCC, the current study investigated bradykinin-induced EGFR transactivation, MAPK activation, and COX-2 expression in human HNSCC cells. Bradykinin induced a concentration- and time-dependent induction of COX-2 protein in HNSCC, which was preceded by phosphorylation of EGFR and MAPK. These effects were abolished by the B2 receptor (B2R) antagonist HOE140 but not by the B1 receptor (B1R) antagonist Lys-[Leu(8)]des-Arg(9)-bradykinin. COX-2 induction was accompanied by increased release of prostaglandin E(2). No effect of a B1R agonist (des-Arg(9)-bradykinin) on p-MAPK or COX-2 expression was observed. B2R protein was found to be expressed in all four head and neck cell lines tested. Immunohistochemical analysis and immunoblot analysis revealed that B2R, but not B1R, was significantly overexpressed in HNSCC tumors compared with levels in normal mucosa from the same patient. In HNSCC cells, the bradykinin-induced expression of COX-2 was inhibited by the EGFR kinase inhibitor gefitinib or mitogen-activated protein kinase kinase inhibitors (PD98059 or U0126). These results suggest that EGFR and MAPK are required for COX-2 induction by bradykinin. Up-regulation of the B2R in head and neck cancers suggests that this pathway is involved in HNSCC tumorigenesis.
Zhang
Weiping
W
Department of Pharmacology and Chemical Biology, University of Pittsburgh, 200 Lothrop Street, Pittsburgh, PA 15261, USA.
Bhola
Neil
N
Kalyankrishna
Shailaja
S
Gooding
William
W
Hunt
Jennifer
J
Seethala
Raja
R
Grandis
Jennifer R
JR
Siegfried
Jill M
JM
D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000235:genetics* / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D043782:Receptor, Bradykinin B2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology
D043782:Receptor, Bradykinin B2; D051546:Cyclooxygenase 2; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases; D015232:Dinoprostone