title: Cyclooxygenase-2 up-regulates vascular endothelial growth factor via a protein kinase C pathway in non-small cell lung cancer.
abstract: BACKGROUND
  Vascular endothelial growth factor (VEGF) expression is up-regulated via a cyclooxygenase-2 (COX-2)-dependent mechanism in non-small cell lung cancer (NSCLC), but the specific signaling pathway involved is unclear. Our aim was to investigate the signaling pathway that links COX-2 with VEGF up-regulation in NSCLC.
  
  
  METHODS
  COX-2 expression in NSCLC samples was detected immunohistochemically, and its association with VEGF, microvessel density (MVD), and other clinicopathological characteristics was determined. The effect of COX-2 treatment on the proliferation of NSCLC cells (A549, H460 and A431 cell lines) was assessed using the tetrazolium-based MTT method, and VEGF expression in tumor cells was evaluated by flow cytometry. COX-2-induced VEGF expression in tumor cells was monitored after treatment with inhibitors of protein kinase C (PKC), PKA, prostaglandin E2 (PGE2), and an activator of PKC.
  
  
  RESULTS
  COX-2 over-expression correlated with MVD (P = 0.036) and VEGF expression (P = 0.001) in NSCLC samples, and multivariate analysis demonstrated an association of VEGF with COX-2 expression (P = 0.001). Exogenously applied COX-2 stimulated the growth of NSCLCs, exhibiting EC50 values of 8.95 × 10(-3), 11.20 × 10(-3), and 11.20 × 10(-3) μM in A549, H460, and A431 cells, respectively; COX-2 treatment also enhanced tumor-associated VEGF expression with similar potency. Inhibitors of PKC and PGE2 attenuated COX-2-induced VEGF expression in NLCSCs, whereas a PKC activator exerted a potentiating effect.
  
  
  CONCLUSIONS
  COX-2 may contribute to VEGF expression in NSCLC. PKC and downstream signaling through prostaglandin may be involved in these COX-2 actions.
authors.affiliation: Department of Thoracic Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou (510080), Guangdong, People's Republic of China.
authors.forename: Honghe
authors.initials: H
authors.lastname: Luo
authors.forename: Zhenguang
authors.initials: Z
authors.lastname: Chen
authors.forename: Hui
authors.initials: H
authors.lastname: Jin
authors.forename: Mei
authors.initials: M
authors.lastname: Zhuang
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Chunhua
authors.initials: C
authors.lastname: Su
authors.forename: Yiyan
authors.initials: Y
authors.lastname: Lei
authors.forename: Jianyong
authors.initials: J
authors.lastname: Zou
authors.forename: Beilong
authors.initials: B
authors.lastname: Zhong
mesh_terms: D000328:Adult; D000368:Aged; D002227:Carbazoles / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D051546:Cyclooxygenase 2 / Q000096:biosynthesis* / Q000494:pharmacology; D020536:Enzyme Activators / Q000494:pharmacology; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011458:Prostaglandins E / Q000819:agonists / Q000037:antagonists & inhibitors; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011758:Pyrroles / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*; D044004:Xanthones / Q000494:pharmacology
chemical_list: D002227:Carbazoles; D020536:Enzyme Activators; D011458:Prostaglandins E; D011758:Pyrroles; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D044004:Xanthones; C053876:6-isopropoxy-9-oxoxanthene-2-carboxylic acid; C057416:KT 5720; D051546:Cyclooxygenase 2; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate