Lysophosphatidic acid acyltransferase-beta is a prognostic marker and therapeutic target in gynecologic malignancies.

Abstract

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.

• Authors: Gregory M Springett, Lynn Bonham, Amanda Hummer, Irina Linkov, Dipika Misra, Chia Ma, Gabriella Pezzoni, Stefano Di Giovine, Jack Singer, Hiroaki Kawasaki, David Spriggs, Robert Soslow, Jakob Dupont
• Journal: Cancer research (Cancer Res) Vol. 65 Issue 20 Pg. 9415-25 (Oct 15 2005) ISSN: 0008-5472 [Print] United States
• PMID: 16230405 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Biomarkers, Tumor
• CT-32228
• Enzyme Inhibitors
• Hydrocarbons, Halogenated
• RNA, Small Interfering
• Triazines
• Acyltransferases
• 2-acylglycerophosphate acyltransferase
• Protein Kinases
• MTOR protein, human
• mTOR protein, mouse
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases

Topics

• Acyltransferases (antagonists & inhibitors, biosynthesis, genetics)
• Animals
• Biomarkers, Tumor (biosynthesis)
• Cell Line, Tumor
• Enzyme Inhibitors (pharmacology)
• Female
• Genital Neoplasms, Female (drug therapy, enzymology, genetics)
• Humans
• Hydrocarbons, Halogenated (pharmacology)
• Mice
• Phosphatidylinositol 3-Kinases (metabolism)
• Prognosis
• Protein Kinases (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• RNA, Small Interfering (genetics)
• Signal Transduction
• TOR Serine-Threonine Kinases
• Triazines (pharmacology)
• Up-Regulation
• Xenograft Model Antitumor Assays