Abstract 4275: PLA2 activities in human epithelial ovarian cancer ascites

Ascites production is characteristic of late stage human epithelial ovarian cancer (EOC) and it correlates with tumor spread clinically. However, the role of this microenvironment in cancer cells and the mechanisms by which ascites promotes tumor development are not well understood. In recent years, phospholipase A 2 (PLA 2 ) enzymes have been identified as cancer therapeutic targets focusing mainly on secreted PLA 2 s (sPLA 2 s). In this work, we optimized and validated the quantitative analytic methods to measure PLA 2 activities in human EOC ascites and tissues. We found, for the first time, that both cytosolic PLA 2 (cPLA 2 ) and calcium-independent PLA 2 (iPLA 2 ), but not sPLA 2 and autotaxin (ATX), activities (not their expression levels) in human EOC tissues and ascites (the tumor microenvironment) were significantly elevated. In addition, while cell-free (S1) and vesicle-free (S4) human EOC ascites had potent promoting activities in proliferation, migration, and invasion of human EOC cells, the PLA 2 activities were involved and account for a significant portion of these activities. Moreover, in vivo studies demonstrated that methyl arachidonyl fluorophosphonate (MAFP, a dual inhibitor of cPLA 2 and iPLA 2 ), was highly effective in inhibiting EOC tumorigenesis/metastasis in xenograft models, supporting PLA 2 activities as new targets for EOC. LPA, an enzymatic product of ATX and PLA 2 enzymes, mediates a significant part of the cellular effects of ascites as evidenced by 1) LPA is produced in cell-free ascites; 2) LPA production and their sensitivities to inhibitors correlate well with the cellular effects in ascites; and 3) the cellular activities were sensitive to LPAR inhibitor and siRNA against LPARs. While cPLA 2 and iPLA 2 are cytosolic enzymes, our findings indicate that they are associated with cell- and microvesicle-free ascites. In summary, our work implies the potential marker and therapeutic values of PLA 2 activity in ovarian cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4275. doi:1538-7445.AM2012-4275