title: Autocrine vascular endothelial growth factor/vascular endothelial growth factor receptor-2 growth pathway represents a cyclooxygenase-2-independent target for the cyclooxygenase-2 inhibitor NS-398 in colon cancer cells.
abstract: OBJECTIVE
  Coexpression of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor-2 (VEGFR-2) has been reported in tumor cells, suggesting the presence of an autocrine VEGF/VEGFR-2 growth pathway in solid tumors. Thus, we hypothesize that the presence of this autocrine pathway in colon cancer cells may be a COX-2-independent target of COX-2 inhibitors and a mechanism behind the antitumor effects of these agents.
  
  
  METHODS
  COX-2-positive (Caco2, HT-29) and COX-2-negative colon cancer cells (DLD-1, Hct-15) were used. Expression of VEGFR-2 was evaluated by Western blot and reverse transcriptase-polymerase chain reaction and VEGF production was measured from culture supernatant by enzyme-linked immunosorbent assay. Growth inhibition and the expression of VEGF and VEGFR-2 were compared after treatment with the COX-2 inhibitor, NS-398 at doses ranging from 5 to 100 microM.
  
  
  RESULTS
  VEGF and VEGFR-2 were expressed in all four colon cancer cells and a blockade of VEGFR-2 with anti-VEGFR-2 antibody treatment induced growth inhibition of colon cancer cells, supporting the presence of autocrine VEGF/VEGFR-2 growth pathway. NS-398 suppressed the growth of colon cancer cells, independent of COX-2 expression. VEGFR-2 expression of tumor cells was reduced after NS-398 treatment at 100 microM, the concentration at which maximal growth inhibition was induced. The amount of VEGF in culture supernatant was increased by NS-398 at 100 microM, suggesting increased secretion of VEGF in compensation for reduced VEGFR-2 expression.
  
  
  CONCLUSIONS
  The autocrine VEGF/VEGFR-2 growth pathway could be a COX-2-independent target of the COX-2 inhibitor, NS-398, in colon cancer cells.
authors: Division of Oncology and Hematology, Department of Internal Medicine, College of Medicine, Korea University, Kozan-1 Dong, Ansan City, Kyoung-ki, Seoul, Korea.
authors: Seok Jin
authors: SJ
authors: Kim
authors: Jae Hong
authors: JH
authors: Seo
authors: Yoo Jung
authors: YJ
authors: Lee
authors: Ji Hye
authors: JH
authors: Yoon
authors: Chul Won
authors: CW
authors: Choi
authors: Byung Soo
authors: BS
authors: Kim
authors: Sang Won
authors: SW
authors: Shin
authors: Yeul Hong
authors: YH
authors: Kim
authors: Jun Suk
authors: JS
authors: Kim
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D018938:Caco-2 Cells; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019073:HT29 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism; D009578:Nitrobenzenes / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects* / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D016861:Cyclooxygenase Inhibitors; D009578:Nitrobenzenes; D013449:Sulfonamides; D042461:Vascular Endothelial Growth Factor A; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D040301:Vascular Endothelial Growth Factor Receptor-2