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Mol Cancer Ther. 2003;2:1067-1078
© 2003 American Association for Cancer Research

Inhibition of lysophosphatidic acid acyltransferase ß disrupts proliferative and survival signals in normal cells and induces apoptosis of tumor cells

Michael Coon1, Alexey Ball1, Jeannine Pound1, Sophe Ap1, David Hollenback1, Thayer White1, John Tulinsky1, Lynn Bonham1, Deborah K. Morrison2, Robert Finney3 and Jack W. Singer1

1 Cell Therapeutics, Seattle, WA; 2 Regulation of Cell Growth Laboratory, NCI-Frederick, MD; and 3 PanGenex, Seattle, WA

Requests for Reprints:Michael Coon, Cell Therapeutics, Seattle, WA 98117. E-mail: mcoon{at}ctiseattle.com

Lysophosphatidic acid acyltransferase ß (LPAAT-ß) 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-ß in Xenopus oocyte meiotic maturation assays and an isoform-specific inhibitor of LPAAT-ß in mammalian cell assays. We found that ectopic overexpression of LPAAT-ß cooperates in activation of the Ras/Raf/Erk pathway in Xenopus oocytes and that inhibition of LPAAT-ß inhibits signaling in both the Ras/Raf/Erk and PI3K/Akt pathways. When LPAAT-ß 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-ß plays an important role in signaling pathways critical to tumor cell survival.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 M. Coon, A. Ball, J. Pound, D. Hollenback, and J.W. Singer.RNA:Knockdown of lysophosphatidic acid acyltransferase-beta (LPAAT-ß) inhibits proliferation and induces apoptosis in tumor cell lines, submitted for publication.

Received 3/12/03; revised 5/19/03; accepted 6/20/03.




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