Inhibition of lysophosphatidic acid acyltransferase beta disrupts proliferative and survival signals in normal cells and induces apoptosis of tumor cells.
Lysophosphatidic acid acyltransferase beta (LPAAT-beta) is an intrinsic membrane protein that catalyzes the synthesis of phosphatidic acid (PA) from lysoPA. Given that PA is a cofactor in a number of signaling cascades that are constitutively active in tumors, we evaluated the role of PA produced by LPAAT-beta in Xenopus oocyte meiotic maturation assays and an isoform-specific inhibitor of LPAAT-beta in mammalian cell assays. We found that ectopic overexpression of LPAAT-beta cooperates in activation of the Ras/Raf/Erk pathway in Xenopus oocytes and that inhibition of LPAAT-beta inhibits signaling in both the Ras/Raf/Erk and PI3K/Akt pathways. When LPAAT-beta activity is suppressed by CT32228 (N-(4-bromo-phenyl)-6-(5-chloro-2-methyl-phenyl)-[1,3,5]triazine-2,4-diamine), an isoform-specific noncompetitive inhibitor, tumor cells undergo mitotic catastrophe while most normal cells simply arrest or become quiescent. The data presented here suggest that PA produced by LPAAT-beta plays an important role in signaling pathways critical to tumor cell survival.
Coon
Michael
M
Cell Therapeutics, Seattle, WA 98117, USA. mcoon@ctiseattle.com
Ball
Alexey
A
Pound
Jeannine
J
Ap
Sophe
S
Hollenback
David
D
White
Thayer
T
Tulinsky
John
J
Bonham
Lynn
L
Morrison
Deborah K
DK
Finney
Robert
R
Singer
Jack W
JW
D000217:Acyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D000818:Animals; D017209:Apoptosis; D002455:Cell Division; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D020128:Inhibitory Concentration 50; D020935:MAP Kinase Signaling System; D008938:Mitosis; D008956:Models, Chemical; D009865:Oocytes / Q000378:metabolism; D010766:Phosphorylation; D020033:Protein Isoforms; D021381:Protein Transport; D015398:Signal Transduction; D013347:Subcellular Fractions; D014981:Xenopus
D020033:Protein Isoforms; D000217:Acyltransferases; C018764:2-acylglycerophosphate acyltransferase