Lysophosphatidic acid acyltransferase-β is a prognostic marker and therapeutic target in gynecologic malignancies Journal Article
| Authors: | Springett, G. M.; 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. |
| Article Title: | Lysophosphatidic acid acyltransferase-β is a prognostic marker and therapeutic target in gynecologic malignancies |
| Abstract: | 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 eradometrial 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. ©2005 American Association for Cancer Research. |
| Keywords: | signal transduction; mitogen activated protein kinase; protein kinase b; cancer survival; controlled study; protein expression; unclassified drug; human cell; cisplatin; raf protein; cancer growth; nonhuman; endometrium cancer; protein localization; animal cell; animals; mice; apoptosis; enzyme inhibition; ovary cancer; protein kinases; tumor markers, biological; animal experiment; animal model; small interfering rna; rna, small interfering; drug structure; tumor xenograft; xenograft model antitumor assays; enzyme activity; cell line, tumor; cancer model; genital neoplasms, female; endoplasmic reticulum; enzyme inhibitors; mammalian target of rapamycin; 1-phosphatidylinositol 3-kinase; proto-oncogene proteins c-akt; autocrine effect; paracrine signaling; protein kinase c; ras protein; drug cytotoxicity; up-regulation; gynecologic cancer; diacylglycerol; acyltransferase; phosphatidic acid; protein kinase c alpha; hydrocarbons, halogenated; acyltransferases; triazines; lysophosphatidic acid acyltransferase beta; acyltransferase inhibitor; ct 32228; ct 32521; lysophosphatidic acid |
| Journal Title: | Cancer Research |
| Volume: | 65 |
| Issue: | 20 |
| ISSN: | 0008-5472 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2005-01-01 |
| Start Page: | 9415 |
| End Page: | 9425 |
| Language: | English |
| DOI: | 10.1158/0008-5472.can-05-0516 |
| PUBMED: | 16230405 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 20" - "Export Date: 24 October 2012" - "CODEN: CNREA" - "Source: Scopus" |
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