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

¹ Drug Discovery Program, Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center, Tampa, Florida; Developmental Chemotherapy Laboratory, Departments of ² Medicine, ³ Biostatistics, ⁴ Pathology and ⁵ Immunohistochemistry Core Laboratory, Memorial Sloan-Kettering Cancer Center, New York, New York; ⁶ Cell Therapeutics Incorporated, Seattle, Washington; and ⁷ Department of Neuropsychiatry, Graduate School of Medical Sciences Kyushu University, Fukuoka, Japan

Requests for reprints: Jakob Dupont, Developmental Chemotherapy Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021. Phone: 212-639-8388; Fax: 212-717-3214; E-mail: dupontj{at}mskcc.org.

Lysophosphatidic acid, the substrate for lysophosphatidic acid acyltransferase ß (LPAAT-ß), 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-ß 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-ß was associated with reduced survival in ovarian cancer and earlier progression of disease in ovarian and endometrial cancer. Inhibition of LPAAT-ß 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-ß also enhanced the survival of mice bearing ovarian tumor xenografts. Cytotoxicity was modulated by diacylglycerol effectors including protein kinase C and CalDAG-GEF1. LPAAT-ß was localized to the endoplasmic reticulum and overexpression was associated with redistribution of protein kinase C-. These findings identify LPAAT-ß as a potential prognostic and therapeutic target in ovarian and endometrial cancer.

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