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Elevated and secreted phospholipase A 2 activities as new potential therapeutic targets in human epithelial ovarian cancer
Author(s) -
Cai Qingchun,
Zhao Zhenwen,
Antalis Caryl,
Yan Libo,
Del Priore Giuseppe,
Hamed Ali Hassan,
Stehman Frederick B.,
Schilder Jeanne M.,
Xu Yan
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.12-207597
Subject(s) - autotaxin , lysophosphatidic acid , ascites , ovarian cancer , cancer research , metastasis , in vivo , carcinogenesis , phospholipase , ovarian carcinoma , phospholipase a , phospholipase a2 , chemistry , biology , cancer , enzyme , medicine , biochemistry , receptor , microbiology and biotechnology
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.—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 A 2 activities as new potential therapeutic targets in human epithelial ovarian cancer. FASEB J. 26, 3306–3320 (2012). www.fasebj.org