Constitutive and lysophosphatidic acid (LPA)-induced LPA production: Role of phospholipase D and phospholipase A₂

Ascitic fluid and plasma from ovarian cancer patients, but not from patients with nongynecological tumors, contain elevated levels of the bioactive phospholipid lysophosphatidic acid (LPA). We show that ovarian cancer cells constitutively produce increased amounts of LPA as compared with normal ovarian epithelium, the precursor of ovarian epithelial cancer, or breast cancer cells. In addition, LPA, but not other growth factors, increases LPA production by the OVCAR-3 ovarian cancer cell line but not by normal ovarian epithelium or breast cancer cell lines. We show that phospholipase D activity contributes to both constitutive and LPA-induced LPA production by ovarian cancer cells. Constitutive and LPA-induced LPA synthesis by ovarian cancer cells is differentially regulated with respect to the requirement of specific phospholipase A2 (PLA₂) subgroups. Group IB (pancreatic) secretory PLA₂ plays a critical role in both constitutive and LPA-induced LPA formation, whereas group IIA (synovial) secretory PLA₂ contributes to LPA-induced LPA production only. Calcium-dependent and/or - independent cytosolic PLA₂s are required for constitutive LPA synthesis but do not play a role in LPA-induced LPA formation. LPA increases the proliferation of ovarian cancer cells, decreases sensitivity to cisplatin, the most commonly used drug in ovarian cancer, decreases apoptosis and anoikis, increases protease production, and increases production of neovascularization mediators. Thus, an understanding of the source and regulation of LPA production in ovarian cancer patients could identify novel targets for therapy.