Constitutive and lysophosphatidic acid (LPA)-induced LPA production: Role of phospholipase D and phospholipase A(2)

Ascitic fluid and plasma from ovarian cancer patients, but not from patient s with nongynecological tumors, contain elevated levels of the bioactive ph ospholipid lysophosphatidic acid (LPA). We show that ovarian cancer cells c onstitutively produce increased amounts of LPA. as compared with normal ova rian epithelium, the precursor of ovarian epithelial cancer, or breast canc er cells. In addition, LPA, but not other growth factors, increases LPA pro duction by the OVCAR-3 ovarian cancer cell line but not by normal ovarian e pithelium or breast cancer cell lines. We show that phospholipase D activit y contributes to both constitutive and LPA-induced LPA production by ovaria n cancer cells. Constitutive and LPA-induced LPA synthesis by ovarian cance r cells is differentially regulated with respect to the requirement of spec ific phospholipase A2 (PLA(2)) subgroups. Group IB (pancreatic) secretory P LA(2) plays a critical role in both constitutive and LPA-induced LPA format ion, whereas group IIA (synovial) secretory PLA(2) contributes to LPA-induc ed LPA production only. Calcium-dependent and/or -independent cytosolic PLA (2)s are required for constitutive LPA synthesis but do not play a role in LPA-induced LPA formation. LPA increases the proliferation of ovarian cance r cells, decreases sensitivity to cisplatin, the most commonly used drug in ovarian cancer, decreases apoptosis and anoikis, increases protease produc tion, and increases production of neovascularization mediators. Thus, an un derstanding of the source and regulation of LPA production in ovarian cance r patients could identify novel targets for therapy.