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 A2 (PLA2)enzymes. The contribution o...

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Bibliographic Details
Published in:The FASEB journal 2012-08, Vol.26 (8), p.3306-3320
Main Authors: Cai, Qingchun, Zhao, Zhenwen, Antalis, Caryl, Yan, Libo, Del Priore, Giuseppe, Hamed, Ali Hassan, Stehman, Frederick B., Schilder, Jeanne M., Xu, Yan
Format: Article
Language:English
Subjects:
Animals
Arachidonic Acids - therapeutic use
ascites
Ascites - pathology
Ascites - physiopathology
autotaxin
Carcinoma, Ovarian Epithelial
Cell Line, Tumor
Female
Humans
Lysophospholipids
methyl arachidonyl fluorophosphonate
Mice
migration
Neoplasm Transplantation
Neoplasms, Glandular and Epithelial - drug therapy
Neoplasms, Glandular and Epithelial - pathology
Neoplasms, Glandular and Epithelial - physiopathology
Organophosphonates - therapeutic use
Ovarian Neoplasms - drug therapy
Ovarian Neoplasms - pathology
Ovarian Neoplasms - physiopathology
Phospholipases A2, Secretory
Phosphoric Diester Hydrolases - metabolism
Research Communications
Transplantation, Heterologous
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Summary: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 A2 (PLA2)enzymes. The contribution of PLA2 activities to ovarian tumorigenesis was investigated. The quantitative measurement of PLA2 activities in ascites and tissues, as well as assay conditions selective for PLA2 subtypes, were optimized and validated. PLA2 activities correlated with tumor‐promoting activates in cell‐based and in vivo assays. High activities consistent with both cytosolic and calcium‐independent PLA2 were found in human EOC ascites for the first time. Elevated PLA2 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 PLA2‐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. PLA2 activity was found in conditioned media from both EOC cells and macrophages. Collectively, our work implies that PLA2 activity is a potential marker and therapeutic target in EOC.—Cai, Q., Zhao, Z., Antalis, C., Yan, L., Del Priore, G., Hamed, A. H., Stehman, F. B., Schilder, J. M., Xu, Y. Elevated and secreted phospholipase A2 activities as new potential therapeutic targets in human epithelial ovarian cancer. FASEB J. 26, 3306–3320 (2012). www.fasebj.org
ISSN:0892-6638
1530-6860
DOI:10.1096/fj.12-207597