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: Qingchun Cai, Zhenwen Zhao, Caryl Antalis, Libo Yan, Giuseppe Del Priore, Ali Hassan Hamed, Frederick B Stehman, Jeanne M Schilder, Yan Xu
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 26 Issue 8 Pg. 3306-20 (Aug 2012) ISSN: 1530-6860 [Electronic] United States
• PMID: 22767227 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Arachidonic Acids
• Lysophospholipids
• Organophosphonates
• methyl arachidonylfluorophosphonate
• Phospholipases A2, Secretory
• Phosphoric Diester Hydrolases
• alkylglycerophosphoethanolamine phosphodiesterase
• lysophosphatidic acid

Topics

• Animals
• Arachidonic Acids (therapeutic use)
• Ascites (pathology, physiopathology)
• Carcinoma, Ovarian Epithelial
• Cell Line, Tumor
• Female
• Humans
• Lysophospholipids
• Mice
• Neoplasm Transplantation
• Neoplasms, Glandular and Epithelial (drug therapy, pathology, physiopathology)
• Organophosphonates (therapeutic use)
• Ovarian Neoplasms (drug therapy, pathology, physiopathology)
• Phospholipases A2, Secretory
• Phosphoric Diester Hydrolases (metabolism)
• Transplantation, Heterologous