title: Effects of cytochrome P450 arachidonic acid epoxygenases on the proliferation of tumor cells.
abstract: OBJECTIVE
  Cytochrome P450 (CYP) arachidonic acid epoxygenases promote cell proliferation and inhibit apoptosis in endothelial cells. This study was to investigate the effects of CYP epoxygenases on the proliferation of tumor cells and possible signaling pathways.
  
  
  METHODS
  The effects of recombinant adeno-associated virus (rAAV) mediated cytochrome P450 2J2 (CYP2J2), cytochrome P450 F87V (CYPF87V) and anti-CYP2J2 on proliferation of Tca-8113, A549, Ncl-H446 and HepG2 cells were measured using MTT and flow cytometry. Expressions of phosphorylated epidermal growth factor receptor (EGFR), extracellular signal-regulated kinase (ERK)1/2 and Akt before and after transfection were detected by western blot. Tca-8113 cells infected with rAAV-CYP2J2, rAAV-CYPF87V, rAAV-antiCYP2J2 and rAAV-GFP were inoculated into nude mice, to observe the effect of CYP epoxygenases on the growth of xenografts.
  
  
  RESULTS
  Infection of Tca-8113, A549, Ncl-H446 and HepG2 cells with rAAV-CYP2J2 and rAAVCYPF87V significantly increased the proliferation of tumor cells by 1.7-, 1.4-, 1.6- and 2.2-fold, and 2.0-, 1.5-, 1.8- and 2.0-fold respectively, as compared with control cells. On the contrary, infection with rAAV-antiCYP2J2 inhibited the proliferation of the four tumor cell lines. Moreover, CYP epoxgenases remarkably enhanced phosphorylation of EGFR, ERK1/2 and Akt, and upregulated total PI3K by 2-, 2.3-, 2.4- and 1.9-fold in the four cell lines, while rAAV-antiCYP2J2 exerted an inhibition effect. Infection of CYP450 epoxygenase genes markedly increased the cell percentage in S/G(2)/M phases by 210% as compared to control Tca-8113 cells. rAAV-CYP2J2 and rAAV-CYPF87V promoted tumor growth of Tca-8113 cell xenografts in nude mice in comparison to the control and rAAV-antiCYP2J2 groups.
  
  
  CONCLUSIONS
  CYP epoxygenases efficiently promote the proliferation of tumor cells, which may be related with the activation of EGFR, ERK1/2 and PI3K/Akt signaling pathways.
authors.affiliation: Department of Internal Medicine, Tongji Hospital, Tongji Medical School, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Jian-Gang
authors.initials: JG
authors.lastname: Jiang
authors.forename: Gui-Fen
authors.initials: GF
authors.lastname: Shen
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
authors.forename: Xian-Ning
authors.initials: XN
authors.lastname: Fu
authors.forename: Dao-Wen
authors.initials: DW
authors.lastname: Wang
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000090762:Cytochrome P-450 CYP2J2; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D053280:Diynes; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000032:analysis; D048049:Extracellular Signal-Regulated MAP Kinases / Q000032:analysis; D005231:Fatty Acids, Unsaturated; D006801:Humans; D051379:Mice; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000032:analysis; D014162:Transfection; D014183:Transplantation, Heterologous
chemical_list: D000090762:Cytochrome P-450 CYP2J2; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D053280:Diynes; D004791:Enzyme Inhibitors; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D005231:Fatty Acids, Unsaturated; D019869:Phosphatidylinositol 3-Kinases; C119440:16-hydroxy-9,17-octadecadiene-12,14-diynoic acid; C000717350:CYP2J2 protein, human