| Autor: |
Springett GM; Memorial Sloan-Kettering Cancer Center, Developmental Chemotherapy Laboratory, Department of Medicine, New York, New York [corrected] USA., Bonham L, Hummer A, Linkov I, Misra D, Ma C, Pezzoni G, Di Giovine S, Singer J, Kawasaki H, Spriggs D, Soslow R, Dupont J |
| Jazyk: |
angličtina |
| Zdroj: |
Cancer research [Cancer Res] 2005 Oct 15; Vol. 65 (20), pp. 9415-25. |
| DOI: |
10.1158/0008-5472.CAN-05-0516 |
| Abstrakt: |
Lysophosphatidic acid, the substrate for lysophosphatidic acid acyltransferase beta (LPAAT-beta), 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-beta 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-beta was associated with reduced survival in ovarian cancer and earlier progression of disease in ovarian and endometrial cancer. Inhibition of LPAAT-beta 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-beta also enhanced the survival of mice bearing ovarian tumor xenografts. Cytotoxicity was modulated by diacylglycerol effectors including protein kinase C and CalDAG-GEF1. LPAAT-beta was localized to the endoplasmic reticulum and overexpression was associated with redistribution of protein kinase C-alpha. These findings identify LPAAT-beta as a potential prognostic and therapeutic target in ovarian and endometrial cancer. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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