Lysophosphatidic Acid Acyltransferase-β Is a Prognostic Marker and Therapeutic Target in Gynecologic Malignancies

Lysophosphatidic acid, the substrate for lysophosphatidic acid acyltransferase β (LPAAT-β), is a well-studied autocrine/paracrine signaling molecule that is secreted by ovarian cancer cells and is found at elevated levels in the blood and ascites fluid of women with ovarian cancer. LPAAT-β converts lysophosphatidic acid to phosphatidic acid, which functions as a cofactor in Akt/mTOR and Ras/Raf/Erk pathways. We report that elevated expression of LPAAT-β was associated with reduced survival in ovarian cancer and earlier progression of disease in ovarian and endometrial cancer. Inhibition of LPAAT-β using small interfering RNA or selective inhibitors, CT32521 and CT32228, two small-molecule noncompetitive antagonists representing two different classes of chemical structures, induces apoptosis in human ovarian and endometrial cancer cell lines in vitro at pharmacologically tenable nanomolar concentrations. Inhibition of LPAAT-β also enhanced the survival of mice bearing ovarian tumor xenografts. Cytotoxicity was modulated by diacylglycerol effectors including protein kinase C and CalDAG-GEF1. LPAAT-β was localized to the endoplasmic reticulum and overexpression was associated with redistribution of protein kinase C-α. These findings identify LPAAT-β as a potential prognostic and therapeutic target in ovarian and endometrial cancer.