arachidonyltrifluoromethane and Adenocarcinoma

In ovarian cancer, the molecular targeted chemotherapeutics could increase the efficiency of low-dose radiotherapy while decreasing injury to adjusted organs. In irradiated A2780 human ovarian carcinoma cells, cytosolic phospholipase A2 (cPLA(2)) inhibitor AACOCF(3) prevented activation of pro-survival Akt signaling and enhanced cell death. The potential molecular mechanisms of this effect could involve signaling through lysophosphatidic acid receptors. In the heterotopic A2780 tumor model using nude mice, cPLA(2) inhibition significantly delayed tumor growth compared to treatment with radiation or vehicle alone. These results identify cPLA(2) as a molecular target to enhance the therapeutic ratio of radiation in ovarian cancer.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Arachidonic Acids; Blotting, Western; Combined Modality Therapy; Cytoplasm; Enzyme Activation; Enzyme Inhibitors; Female; Humans; Mice; Mice, Nude; Ovarian Neoplasms; Phospholipases A2, Cytosolic; Radiation-Sensitizing Agents; Signal Transduction; Xenograft Model Antitumor Assays

We have shown that NADPH oxidase NOX5-S is overexpressed in Barrett's esophageal adenocarcinoma (EA) cells and may contribute to the progression from Barrett's esophagus (BE) to EA presumably by increasing cell proliferation and decreasing apoptosis (Fu X, Beer DG, Behar J, Wands J, Lambeth D, Cao W. J Biol Chem 281: 20368-20382, 2006). The mechanism(s) of NOX5-S overexpression in EA, however, is not fully understood. In SEG1 EA cells we found that acid treatment significantly increased platelet-activating factor (PAF) production, which in turn markedly increased NOX5-S expression and hydrogen peroxide (H(2)O(2)) production. Knockdown of NOX5-S by NOX5-S small interfering RNA (siRNA) blocked PAF-dependent H(2)O(2) production. PAF-dependent induction of NOX5-S expression and H(2)O(2) production were significantly decreased by the MAPK kinase 1 inhibitor PD-98059, by the cytosolic phospholipase A(2) (cPLA(2)) inhibitor AACOCF3, and by STAT5 downregulation with STAT5 siRNA. PAF significantly increased the phosphorylation of ERK1/2 MAPK, cPLA(2), and STAT5. Using inhibitors, we demonstrated that PAF-induced STAT5 phosphorylation depends on activation of ERK1/2 MAPK and cPLA(2), whereas PAF-induced cPLA(2) phosphorylation was associated with activation of ERK1/2 MAPK. Given that STAT5 bound to the c-sis-inducible element (TTCTGGTAA) of the NOX5-S promoter, overexpression of STAT5 significantly increased NOX5-S promoter activity. We conclude that acid-induced NOX5-S expression and H(2)O(2) production is mediated in part by production of PAF in SEG1 EA cells, and that PAF-induced increase in NOX5-S expression depends on sequential activation of ERK MAP kinases, cPLA(2), and STAT5 in these cells.

Topics: Adenocarcinoma; Arachidonic Acids; Barrett Esophagus; Cell Line, Tumor; Enzyme Inhibitors; Esophageal Neoplasms; Flavonoids; Humans; Hydrogen Peroxide; Hydrogen-Ion Concentration; MAP Kinase Kinase 1; Membrane Proteins; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; NADPH Oxidase 5; NADPH Oxidases; Phospholipases A2, Cytosolic; Phospholipid Ethers; Phosphorylation; Platelet Activating Factor; Platelet Aggregation Inhibitors; Promoter Regions, Genetic; RNA Interference; RNA, Small Interfering; Signal Transduction; STAT5 Transcription Factor; Transfection; Up-Regulation