title: Elevated and secreted phospholipase A₂ activities as new potential therapeutic targets in human epithelial ovarian cancer.
abstract: Ascites in epithelial ovarian cancer (EOC) promotes tumor development by mechanisms that are incompletely understood. Lysophosphatidic acid (LPA), a major tumor-promoting factor in EOC ascites, is an enzymatic product of autotaxin (ATX) and phospholipase A(2) (PLA(2))enzymes. The contribution of PLA(2) activities to ovarian tumorigenesis was investigated. The quantitative measurement of PLA(2) activities in ascites and tissues, as well as assay conditions selective for PLA(2) subtypes, were optimized and validated. PLA(2) activities correlated with tumor-promoting activates in cell-based and in vivo assays. High activities consistent with both cytosolic and calcium-independent PLA(2) were found in human EOC ascites for the first time. Elevated PLA(2) and ATX activities were also observed in EOC compared to benign tumors and normal tissues. Cell-free and vesicle-free (S4) human EOC ascites potently promoted proliferation, migration, and invasion of human EOC cells in a PLA(2)-dependent manner. LPA mediated a significant part of the cell-stimulating effects of ascites. S4 ascites stimulated tumorigenesis/metastasis in vivo, and methyl arachidonyl fluorophosphonate was highly effective in inhibiting EOC metastasis in mouse xenograft models. PLA(2) activity was found in conditioned media from both EOC cells and macrophages. Collectively, our work implies that PLA(2) activity is a potential marker and therapeutic target in EOC.
authors: Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis,Indiana 46202, USA.
authors: Qingchun
authors: Q
authors: Cai
authors: Zhenwen
authors: Z
authors: Zhao
authors: Caryl
authors: C
authors: Antalis
authors: Libo
authors: L
authors: Yan
authors: Giuseppe
authors: G
authors: Del Priore
authors: Ali Hassan
authors: AH
authors: Hamed
authors: Frederick B
authors: FB
authors: Stehman
authors: Jeanne M
authors: JM
authors: Schilder
authors: Yan
authors: Y
authors: Xu
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000627:therapeutic use; D001201:Ascites / Q000473:pathology / Q000503:physiopathology; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008246:Lysophospholipids; D051379:Mice; D009368:Neoplasm Transplantation; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D063065:Organophosphonates / Q000627:therapeutic use; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D054497:Phospholipases A2, Secretory; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D014183:Transplantation, Heterologous; D000099189:Lysophospholipase D
chemical_list: D001095:Arachidonic Acids; D008246:Lysophospholipids; D063065:Organophosphonates; D054497:Phospholipases A2, Secretory; D010727:Phosphoric Diester Hydrolases; D000099189:Lysophospholipase D; C104810:methyl arachidonylfluorophosphonate; C032881:lysophosphatidic acid