Pla(2) Activities In Human Epithelial Ovarian Cancer Ascites

Abstract 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 A2 (PLA2) enzymes have been identified as cancer therapeutic targets focusing mainly on secreted PLA2s (sPLA2s). In this work, we optimized and validated the quantitative analytic methods to measure PLA2 activities in human EOC ascites and tissues. We found, for the first time, that both cytosolic PLA2 (cPLA2) and calcium-independent PLA2 (iPLA2), but not sPLA2 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 PLA2 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 cPLA2 and iPLA2), was highly effective in inhibiting EOC tumorigenesis/metastasis in xenograft models, supporting PLA2 activities as new targets for EOC. LPA, an enzymatic product of ATX and PLA2 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 cPLA2 and iPLA2 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 PLA2 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