title: The shunting of arachidonic acid metabolism to 5-lipoxygenase and cytochrome p450 epoxygenase antagonizes the anti-cancer effect of cyclooxygenase-2 inhibition in head and neck cancer cells.
abstract: BACKGROUND
  It has recently been found that 5-lipoxygenase (5-LO) and cytochrome P450-2J2 (CYP2J2), molecules capable of arachidonic acid (AA) metabolism, might promote cancer cell viability through several mechanisms similar to those of cyclooxygenase-2 (COX-2). We found that not only COX-2 expression, but also the expression of 5-LO and CYP2J2 is up-regulated in head and neck squamous cell carcinoma (HNSCC) cell lines. From these observations, we hypothesized that AA metabolism by 5-LO and/or CYP2J2 may lower the efficacy of anti-cancer effect by COX-2 inhibition.
  
  
  RESULTS
  Although COX-2 was highly expressed in all cell lines tested, COX-2-specific inhibition showed little growth-inhibitory effect in some cell lines. Inhibition of COX-2 resulted in increased production of LTB(4) and 14-15-DHET/EET, metabolites of 5-LO and CYP2J2, respectively. Combined knock-down of COX-2 and 5-LO or CYP2J2 by siRNA results in a decrease in cell proliferation and VEGF production. Furthermore, these results are dependent on 5-LO and CYP2J2 expression in cells.
  
  
  CONCLUSIONS
  Therefore, combined inhibition of COX-2 and 5-LO or CYP2J2 may be one way to overcome low efficacy of single inhibition of COX-2 in cancer cells. In addition, combined therapies should be chosen based on the expression of members of other AA metabolism pathways.
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Seok-Woo
authors.initials: SW
authors.lastname: Park
authors.forename: Dae-Seog
authors.initials: DS
authors.lastname: Heo
authors.forename: Myung-Whun
authors.initials: MW
authors.lastname: Sung
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics / Q000378:metabolism*; D016718:Arachidonic Acid / Q000378:metabolism*; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D000090762:Cytochrome P-450 CYP2J2; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D015232:Dinoprostone / Q000096:biosynthesis; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D007975:Leukotriene B4 / Q000096:biosynthesis; D010957:Plasmids / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
chemical_list: C107016:14,15-dihydroxyeicosatrienoic acid; D000970:Antineoplastic Agents; C000717350:CYP2J2 protein, human; D052246:Cyclooxygenase 2 Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D034741:RNA, Small Interfering; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D007975:Leukotriene B4; D016718:Arachidonic Acid; D003577:Cytochrome P-450 Enzyme System; D001094:Arachidonate 5-Lipoxygenase; D000090762:Cytochrome P-450 CYP2J2; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D015126:8,11,14-Eicosatrienoic Acid; D015232:Dinoprostone