Lysophosphatidic acid acyltransferase-beta is a prognostic marker and therapeutic target in gynecologic malignancies.
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.
Springett
Gregory M
GM
Memorial Sloan-Kettering Cancer Center, Developmental Chemotherapy Laboratory, Department of Medicine, New York, New York [corrected] USA.
Bonham
Lynn
L
Hummer
Amanda
A
Linkov
Irina
I
Misra
Dipika
D
Ma
Chia
C
Pezzoni
Gabriella
G
Di Giovine
Stefano
S
Singer
Jack
J
Kawasaki
Hiroaki
H
Spriggs
David
D
Soslow
Robert
R
Dupont
Jakob
J
D000217:Acyltransferases / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D014408:Biomarkers, Tumor / Q000096:biosynthesis*; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005833:Genital Neoplasms, Female / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D006846:Hydrocarbons, Halogenated / Q000494:pharmacology; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011379:Prognosis; D011494:Protein Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D014227:Triazines / Q000494:pharmacology; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
D000217:Acyltransferases; D014408:Biomarkers, Tumor; D004791:Enzyme Inhibitors; D006846:Hydrocarbons, Halogenated; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D058570:TOR Serine-Threonine Kinases; D014227:Triazines; C505793:CT-32228; C018764:2-acylglycerophosphate acyltransferase; C546842:MTOR protein, human; C546843:mTOR protein, mouse