Lysophosphatidic Acid Acyltransferase-β Is a Prognostic Marker and Therapeutic Target in Gynecologic Malignancies
| Autor: | Gregory M. Springett, Chia Ma, Jack W. Singer, Irina Linkov, Amanda J. Hummer, Lynn Bonham, Hiroaki Kawasaki, Dipika Misra, David R. Spriggs, Gabriella Pezzoni, Jakob Dupont, Robert A. Soslow, Stefano Di Giovine |
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| Rok vydání: | 2005 |
| Předmět: |
Cancer Research
medicine.medical_specialty Genital Neoplasms Female Biology Mice Phosphatidylinositol 3-Kinases Paracrine signalling chemistry.chemical_compound Ovarian tumor Cell Line Tumor Internal medicine Lysophosphatidic acid Biomarkers Tumor medicine Animals Humans Enzyme Inhibitors RNA Small Interfering Autocrine signalling Protein kinase B PI3K/AKT/mTOR pathway Diacylglycerol kinase Hydrocarbons Halogenated Triazines TOR Serine-Threonine Kinases Prognosis medicine.disease Xenograft Model Antitumor Assays Up-Regulation Endocrinology Oncology chemistry Cancer research Female Ovarian cancer Protein Kinases Proto-Oncogene Proteins c-akt Acyltransferases Signal Transduction |
| Zdroj: | Cancer Research. 65:9415-9425 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-05-0516 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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